What is the LADMER System?

The LADMER system deals with the complex dynamic processes of

Liberation of an active ingredient from the dosage form
Absorption into systemic circulation
Distribution
Metabolism in the body
Excretion of the drug from the body
Response

What is Liberation
is the delivery of the active ingredient from a dosage form into solution. The dissolution medium is either a biological
fluid or an artificial test fluid (in vitro). Drug release is characterized by the speed and the amount of drug appearing
in solution

Liberation is the first step which determines onset of action, rate of absorption, availability, etc., which is true for
all drug products by all routes of administration, except intravenous and the peroral use of true solutions. Liberation is
controlled by the characteristics of the drug product.

A drug administered in a dosage forms by any route of administration must be released from the dosage
form (except I.V., and true solutions for other routes). In order that a drug can be absorbed it must be
present in the form of solution, therefore dissolution becomes the first and sometimes rate-limiting step.
Upon administration of suspensions, capsules, tablets, suppositories, implants and intramuscular (I.M.)
suspensions, we find drug particles in the gastrointestinal (G.I) tract, in body cavities or in tissue.

Rate Limiting Step is the process with the slowest rate constant in a system of simultaneous kinetic
processes.

What is Absorption
is the process of uptake of the compound from the site of administration into the systemic circulation. A
prerequisite for absorption is that the drug be in aqueous solution.

Site of Absorption
- buccal - intraperitoneal
- sublingual - intracutaneous
- gastrointestinal - ocular
- percutaneous - nasal
- subcutaneous - pulmonal
- intramuscular - rectal

What is Distribution
refers to the transfer of the drug from the blood to extravascular fluids and tissues.

What is Metabolism
is the enzymatic or biochemical transformation of the drug substance to (usually less toxic) metabolic
products, which may be eliminated more readily from the body.

What is Excretion
is the final elimination of the drug substance or its metabolites from the body such as through the kidney
(urine), intestines (feces), skin (sweat), saliva, and/or milk.

What is Response
refers to the therapeutic effect, subtherapeutic effect, side effect and toxic effect.
What is Drug Product Design?
Drugs have been used for centuries for the treatment of diseases. The drug is combined with
other with other ingredients into a drug formulation, which may be a solution, tablet, capsule, or
suppository.

Early civilizations recognized that the way a drug product was prepared could affect the potency
of the active drug. The development of biopharmaceutic principle allowed for the rational design of drug
product, which would enhance the delivery of active drug, and optimize the therapeutic efficacy of the drug
in the patient.
Modern biopharmaceutic is the study of the relationship physiochemical properties and in vitro
behavior of the drug and drug product on the delivery of the drug of the body under normal and pathologic
conditions. Bioavailability refers to the measurement of the rate and extent of active drug that reaches the
systemic circulation. Because blood circulation delivers the therapeutically active drug to the tissues and to
the site of action of the drug, changes in bioavailability affect changes in the pharmacodynamics and toxicity
of the drug
Biopharmaceutic studies allow drugs to be formulated rationally based on the pharmaceutical
properties. These drugs may be applied topically to the skin, nose, eye, mucous membranes, buccal cavity,
throat, and rectum. A drug intended to for local activity may be given intravaginally, into the urethra tract,
intranasally, in the ear, on the eye, or orally.

Biopharmaceutic considerations often determine the ultimate dose and dosage form of the drug
product. In the biopharmaceutics, the rate of drug release from the product, and the rate of drug
absorption, is important in determining the distribution of the drug in the body. Consequently, the various
stages of the drug dissolution, absorption, and distribution are closely monitored using pharmacokinetic
models. Both biopharmaceutic and kinetic principles are applied in the design of dosage form.

RATE-LIMITING STEPS IN DRUG ABSORPTION

Systemic absorption of most drug products consists of a succession of rate processes. These
processes include
(1) disintegration of the drug product and subsequent release of the drug;
(2) dissolution of the drug in an aqueous environment; and
(3) absorption across cell membranes into the systemic circulation. In the process of drug
disintegration, dissolution, and absorption, the rate bioavailability.

The slowest step in a series of kinetic processes is called the rate- limiting step. Except for
sustained-release or prolonged-action product, disintegration of a solid drug product is usually more rapid
than drug dissolution and drug absorption.

PHARMACEUTIC FACTORS AFFECTING DRUG BIOVAILABILITY

In order top design a drug product that will deliver the active drug in the most bioavailable form,
the pharmacist must consider
(1) the type of drug product (eg, solution, suspension, suppository);
(2) the nature of the excipients in the drug product; and
(3) the physicochemical properties of the drug molecule.

Disintegration
It was generally recognized some years ago that a solid drug product had to disintegrate into
small particles and release the drug before absorption could take place. For the purpose of monitoring
uniform tablet disintegration, the United States Pharmacopoeia (USP) established an official disintegration
test. Solid drug products exempted from disintegration tests include troches, tablets, which are intended
to be chewed, and drug products intended for sustained release or prolonged or repeat action.
 The process of disintegration does not imply complete dissolution of the tablet and/or the drug.
Complete disintegration is defined by the USP-XX as that state in which any residue of the tablet, except
fragments of insoluble coating, remaining on the screen of the test apparatus in the soft mass have no
palpable firm core. the official apparatus for the disintegration and procedure in the USP-XX. Separate
specifications are given for uncoated tablets, enteric tablet, buccal tablet, and sublingual tablets.

Dissolution
Dissolution is the process by which a chemical or drug becomes dissolved in a solvent. In biologic
systems, drug dissolution I an aqueous medium is an important prior condition of the systemic absorption.
The rate which drugs with poor aqueous solubility dissolved from an intact or disintegrated solid dosage
form in the gastrointestinal tract often controls the rate of systemic absorption of the drug.
Noyes and Whitney and other investigators studied the rate of dissolution of solid drugs. According
to their observation, the steps in the dissolution include the process of drug dissolution at the surface of
the solid particle, thus forming a saturated solution around the particle. The dissolved drug in the saturated
solution knows as the stagnant layer diffuses to the bulk of the solvent from regions.

Physicochemical Nature of the Drug

The nature of the physical and chemical properties of the solid drug particles has a great effect on the
dissolution kinetics. Because dissolution is though to take place at the surface of the solute, the greater
the surface area, the more rapid the rat of drug dissolution.
The degree of aqueous solubility of the drug also affects the rate of the dissolution. Generally. the
ionizable salt of the drug is more water soluble than the free base The drug may also exist in more than
one of the crystalline forms known as polymorphs, which have identical chemipcal structure, demonstrate
different dissolution kinetics.

Formulation Factors affecting Drug Dissolution

The various excipient in the drug product may also affect dissolution kinetics of the drug either by altering
the medium in which the drug is dissolving or by reacting with the drug itself. Tablet lubricants such as
magnesium stearate may repel water and reduce dissolution when used in large quantities. Surfactants
may, however, affect drug dissolution in an unpredictable fashion. Low concentrations of surfactants lower
the surface tension and increase the rate of drug dissolution, whereas higher concentration of surfactants
tend to form micelles with the drug and thus decrease the dissolution rate.
In addition, the excipients in a formulation may interact directly with the drug to form a water-
soluble complex.

Factors affecting drug transport and absorption

The systemic absorption of a drug is dependent upon:

1. the physicochemical properties of the drug
2. the nature of the drug product
3. anatomy and physiologic functions at the site of drug absorption

NATURE OF THE CELL MEMBRANE

Are a major structure in cells, surrounding the entire cell and acting as a boundary between the cell and
the interstitial fluid.
Enclose most of the cell organelles.
Act as a selective barrier to the passage of molecules.
CELL MEMBRANES are semipermeable membranes; water, some selected small molecules, and lipid
soluble molecules pass through them, whereas highly charged molecules and large molecules such as
proteins and protein bound drugs do not.
 Generally thin, approximately 70 to 100 A in thickness.
Primarily composed of phospholipids with interdispersed carbohydrates and integral protein groups in the
form of a bilayer.
Lipid bilayer or unit membrane theory the cell membrane to be composed of two layers of phospholipids
between two surface layers of proteins. It explains the observation that lipid-soluble drugs tend to penetrate
cell membranes more easily than polar molecules.
Fluid mosaic model the cell membrane consists of globular protein embedded in a dynamic fluid, lipid
bilayer matrix.

PASSAGE OF DRUGS ACROSS CELL MEMBRANES

Passive Diffusion
Is the process by which molecules spontaneously diffuse from a region of higher concentration
to a region of lower concentration.
Is the major transmembrane process for most drugs.
Osmosis can be viewed as the passive diffusion of water, or more generally any solvent, down
its concentration gradient across a selectively permeable membrane.

Active Transport

Is a carrier-mediated transmembrane process

plays an important role in the renal and biliary secretion of many drugs and metabolites.
It characterized by the transport of drug against a concentration gradient that is from regions
of low drug concentrations to regions of high concentrations.
This is an energy-consuming system.
Is a specialized process requiring a carrier that binds the drug to form a carrier drug complex
that shuttles the drug across the membrane and then dissociates the drug on the other side of the
membrane.

Facilitated Diffusion

is also a carrier-mediated transport system, differing from active transport in that the drug moves
along a concentration gradient.
moves from a region of high drug concentration to a region of a low drug concentration
This system does not require energy input. It is saturable and structurally selective for the drug
and shows competition kinetics for drugs of a similar structure.

Vesicular Transport

Is the process of engulfing particles or dissolved materials by the cell.

Pinocytosis refers to the engulfment of small soluted or fluid.
Phagocytosis refers to the engulfment of larger particles or macromolecules generally by
macrophages.
Is the proposed process for the absorption of orally administered sabin polio vaccine and various
large proteins.

Pore (Convective) Transport

Very small molecules (such as urea, water, and sugars) are able to rapidly cross cell membranes
as if the membrane contained channels or pores. A certain type of protein call transport protein
may form an open channel across the lipid membrane of the cell. Small molecules including drugs
move through the channel by diffusion more rapidly than at other parts of the membrane.
Ion Pair Formation

Strong electrolytes drugs are highly ionized or charged molecules, such as quaternary nitrogen
compounds with extreme pKa values, and maintain their charge at all physiologic pH values. These
drugs penetrate membranes poorly. When linked up with an oppositely charged ion, an ion pair is
formed in which the overall charge of the pair id neutral.

Anatomic and Physiologic Considerations

The major physiologic processes that occur in the gastrointestinal system:

1. Secretion includes the transport of fluid, electrolytes, peptides, and proteins into the lumen of
the alimentary canal.
2. Digestion is the breakdown of food constituents into smaller structures in preparation for
absorption.
3. Absorption is the entry of constituents from the lumen of the gut into the body. May be considered
as the net results of both lumen-to-blood and blood-to-lumen transport movements.
Drugs administered orally pass through various parts of the enteral canal including the oral cavity,
esophagus, and various parts of the GI tract. Residues eventually exit the body through the anus.
Total transit time including gastric emptying, small intestinal transit, and colonic transit ranges from
0.4 to 5 days.
The most important site for drug absorption is the small intestine.
Small intestine transit time (SITT) ranges from 3 to 4 hours.
The normal physiologic process of the alimentary canal may be affected by
1. Diet
2. contents of the GI tract
3. hormones
4. the visceral nervous system
5. disease
6. drugs
Oral Cavity
Saliva is the main secretion of the oral cavity, and has a pH of about 7. It contains ptyalin, which
digests starches. About 1500 ml of saliva is secreted per day.
Mucin a glycoprotein that lubricates food is also secreted and may interact with drugs.
Esophagus
The esophagus connects the pharynx and the cardiac orifice of the stomach. The pH of the fluids is
between 5 and 6. The lower part of the esophagus ends with the esophageal sphincter, which prevents
acid reflux from the stomach. Very little drug dissolution occurs in the esophagus.

Stomach
The stomach is innervated by the vagus nerve. The fasting pH of the stomach is about 2 to 6. In the
presence of food, the stomach ph is about 1.5 to 2. Stomach acid secretion is stimulated by gastrin
and histamine. Gastrin release is regulated by stomach distension and the presence of peptides and
amino acids. Stomach emptying influenced by the food content and osmolality.
Duodenum
The duodenal pH is about 6 to 6.5 due to the presence of bicarbonate that neutralizes the acidic chime
emptied from the stomach. The duodenum is a site where many ester prodrugs are hydrolyzed during
absorption. The presence of proteolytic enzymes also makes many protein drugs unstable in the
duodenum, preventing adequate absorption.

Ileum
The ileum is the terminal part of the small intestine. This site has fewer contractions than the
duodenum. The pH is about 7, with the distal part as high as 8.

Colon
The colon lacks microvilli and is very limited in drug absorption due to the more viscous and semisolid
nature of the lumen contents. The colon is lined with mucin functioning as lubricant and protectant.
The pH in this region is 5.5 to 7. Drugs that are absorbed well in this region are good candidates for
an oral sustained-release dosage form. The colon contains both aerobic and anaerobic microorganisms
that may metabolized some drugs.

Rectum
The rectum is about 15 cm, ending the anus. Drug absorption after fecal administration may be variable
depending upon the placement of the suppository or drug solution within the rectum.
Drug Absorption in the Gastrointestinal Tract
Drugs may be absorbed by passive diffusion from all parts of the alimentary canal including sublingual,
buccal, GI, and rectal absorption.
For most drugs, the optimum site for drug absorption after oral administration is the upper portion of
the small intestine or duodenum region.
The large surface area of the duodenum is due to the presence of valve like folds in the mucous
membrane upon, which are small projections known as villi. These villi contain even smaller projections
known as microvilli, forming a brush border.

Gastrointestinal Motility
GI motility tends to move the drug through the alimentary canal so that it may not stay at the
absorption site.
The transit time of the drug in the GI tract depends upon the pharmacologic properties of the drug,
type of the dosage form, and various physiologic factors.
Physiologic movement of the drug within the GI tract depends upon whether the alimentary canal
contains recently ingested food or is in fasted or interdigestive state.

Gastric Emptying Time

The duodenum has the greatest capacity for the absorption of drugs from the GI tract, a delay in the
gastric emptying time for the drug to reach the duodenum will slow the rate and possibly the extent of
drug absorption, thereby prolonging the onset time for the drugs.
INFLUENCE GASTRIC EMPTYING
Factor
1. Volume
2. Type of meal
Fatty acids
Triglycerides
Carbohydrates
Amino acids
3. Osmotic pressure
4. Physical state of gastric contents
5. Chemicals
Acids
Alkali (NaHCO3)
6. Drugs
Anticholinergics
Narcotic analgesics
Metoclopramide
Ethanol
7. Miscellaneous
Body position
Viscosity
Emotional states
Bile salts
Disease states
Exercise
Gastric surgery

Intestinal Motility
Normal peristaltic movements mix the contents of the duodenum, bringing the drug particles into
intimate contact with the intestinal mucosal cells. The drugs must have a sufficient time at the
absorption site for the optimum absorption.
The average normal small intestine transit time was about 7 hours in early studies using indirect
methods based on the detection of hydrogen after an oral dose of lactulose. Newer studies using
gamma scintigraphy have to shown SITT to be about 3 to 4 hours.
A drug may take about 4 to 8 hours to pass through the stomach and small intestine during the fasting
state. During the fed state, SITT may take 8 to 12 hours.
For modified-release or controlled dosage forms, which slowly release the drug over an extended period
of time, the dosage form must stay within a certain segment of the intestinal tract so that the drug
contents are released and absorbed prior to loss of the dosage form in the feces.
Perfusion of the Gastrointestinal Tract
The Splanchnic circulation receives about 28% of the cardiac output and is increased after meals. Once
the drug is absorbed from the small intestine, it enters via mesenteric vessels to the hepatic-portal vein
and the liver prior to reaching the systemic circulation.
Any decrease in mesenteric blood flow, as in the case of congestive heart failure, will decrease the rate
of drug removal from the intestinal tract. Thereby reducing the rate of the drug bioavailability.
The Lymphatic circulation in drug absorption is well absorbed. Drugs are absorbed through the lacteal
or lymphatic vessels under the microvilli.
Absorption of drugs through the lymphatic system bypasses the first-pass effect due to liver
metabolism, because drug absorption through the hepatic portal vein is avoided.
The lymphatic is important in the absorption of dietary lipids and may be partially responsible for the
absorption for some lipophilic drugs.

Effect of food on Gastrointestinal Drug Absorption

The presence of food in the GI tract can affect the bioavailability of the drug. Digested food contains
amino acids, fatty acids, and many nutrients that may affect intestinal pH and solubility of drugs.
The absorption of some antibiotics is decreased with food; whereas other drugs such griseofulvin, are
better absorbed when given with food containing a high fat content.
Bioavailability of drugs is better among patients in the fasted state and with a large volume of water.
The dosage form of the drug may also be affected by the presence of food.
Enteric-coated tablets may stay in the stomach for a longer period of time because food delays stomach
emptying.
Food can also affect the integrity of the dosage form causing an alteration in the release rate of the
drug.

Double-peak Phenomenon
The double-peak phenomenon is generally observed after the administration of a single dose to fasted
patients.
The rationale for the double-peak phenomenon has been attributed to variability in stomach emptying,
variables intestinal motility, presence of food, enterohepatic recycling, or failure of a tablet dosage
form.

Factors affecting drug distribution

When a dose of drug enters the blood, the molecules are distributed through out the body by the
systemic circulation.
The drug molecules are carried to the target site of drug action (receptor) and to other tissues and
organs.
Some drug molecules are distributed to eliminating organs:

Liver, Kidney
Others are distributed to tissues: Brain, Skin, Muscles
The circulatory system consists of series of blood vessels, including the arteries, which carry blood to
tissues; and veins, which return the blood back to the heart.
An average subject (70 kg) has about 5 liters of blood, which is equivalent to 3 liters of plasma.
 An average subject cardiac output is 0.08 L/min x 69 beats/min. Drug molecules rapidly diffuse through
a network of fine capillaries to the tissue spaces filled with interstitial fluid.
Drug distribution is generally rapid, and most small drug molecules permeate capillary membranes
easily.
The passage of drug molecules across a cell membrane depends upon the physicochemical nature of
both the drug and the cell membrane.
Lipid soluble drugs generally diffuse across cell membranes more easily than highly polar or water-
soluble drugs.
Diffusion and Hydrostatic Pressure The process by which drugs transverse capillary membranes.
Passive diffusion is the main process by which most drugs cross cell membranes. It is the process by
which drug molecules move from an area of high concentration to an area of low concentration.

Hydrostatic pressure represents a pressure gradient between the arterial end of the capillaries
entering the tissue and the venous capillaries leaving the tissue. It plays an important role in glomerular
filtration in the kidneys, in which the high arterial pressure and high blood flow allow for small drug
molecules to be filtered in the glomerulus of the renal nephron.
Hydrostatic or filtration pressure The higher pressure at the arterial end of the capillary.
Absorptive pressure The lower pressure of the venous blood compared with the tissue fluid.

Tissue Perfusion and Initial Drug Distribution

After the drug molecules enter the bloodstream, the rate of blood flow perfusion to each tissue and
the affinity of the drug to accumulate in the tissue govern the pattern of drug distribution.
Tissues that receive the highest blood flow will rapidly equilibrate with the drug, whereas tissues that
are poorly perfused will equilibrate with the drug more slowly.
Blood flow is an important factor in determining the initial distribution of drugs.

Drug Accumulation
The accumulation of drug into tissues is dependent upon both blood and tissue affinity for the drug.
The affinity of a drug for a tissue is generally reversible. The tissue concentration of drugs with low
tissue affinity equilibrates rapidly with the plasma drug concentration and declines rapidly as the drug
concentration in the blood is eliminated.
Drugs with high tissue affinity tend to accumulate or concentrate in the tissue.
Drugs with a high lipid/water partition coefficient are highly fat-soluble and tend to accumulate in lipid
tissue.

Drug Distribution and Pharmacodynamics

The pharmacologic effect of the drug depends upon the concentration of the drug at the receptor site,
which in turn depends upon the relative rates of drug access to the receptor and subsequent removal
of the drug from the receptor.
The onset and intensity of drug action is influenced by the initial distribution of the drug and total dose
of the drug given to the patient.
The dose of the drug and the dosage form must be chosen to provide sufficiently high plasma drug
concentrations so that an adequate amount of drugs reaches the site of drug action at a proper rate.
The duration of drug action is mainly influenced by the rate of drug elimination.
Permeability of Cell and Capillary Membranes
Cell membranes vary in their permeability characteristics depending upon the tissue.
The capillary membranes in the liver and kidneys are more permeable to transmembrane drug
movement than capillaries in the brain.
The sinusoidal capillaries of the liver are very permeable and allow the passage of large-molecular-
weight molecules.
In the case of the brain and spinal cord, a layer of glial cells, which have tight intercellular junctions,
surrounds the capillary endothelial cells. This lipid barrier, which slows the diffusion and penetration of
water-soluble and polar drugs into the brain and spinal cord, is called the blood brain barrier.
Under certain pathophysiologic conditions, the permeability of the cell membrane may be altered.
Burns will alter the permeability of skin and allow drugs and larger molecules to permeate inward or
outward.
The diameters of capillaries are very small and the capillary membranes are very thin.
The high blood flow within a capillary allows for intimate contact of drug molecules with the cell
membrane, providing for rapid drug diffusion.
DRUG PROTEIN BINDING
Drug- protein binding The formation a drug protein complex. It may be a reversible or irreversible
process.
Irreversible drug-protein binding - is usually a result of chemical activation of the drug, which then
attaches strongly to the protein or macromolecule by covalent chemical bonding. It accounts for certain
types of drug toxicity that may occur over a long time period as in the case of chemical carcinogenesis.
Reversible drug-protein binding Most drugs bind or complex with proteins by a reversible process.
It implies that the drug binds the protein with weaker chemical bonds such as hydrogen bonds or
van der waals forces.

Drug may bind to various macromolecular components in the blood including:

Albumin
A protein synthesized by the liver with a molecular wt. of 65,000 to 69,000d.
Major component of plasma proteins responsible for reversible drug binding.
Distributed in the plasma and in the extracellular fluids of skin, muscle, and various tissues.
Elimination half-life is 17 to 18 days.
Responsible for maintaining osmotic pressure of the blood and for the transport of endogenous
and exogenous substances.

Alpha acid glycoprotein (orosomucoid)

A globulin with a molecular weight of about 44,000 d.
Plasma concentration is low (0.4 to 1%) and binds primarily basic (cationic) drugs.

Globulins
May be responsible for the transport of certain endogenous substances such as corticosteroids. It
has a low capacity but high affinity for the binding of these endogenous substances.
Lipoproteins
Macromolecular complexes of lipid and proteins and are classified according to their density
and separation in the ultracentrifuge.
Responsible for the transport of plasma lipids and may be responsible for the binding of drugs
if the albumin sites become saturated.

Erythrocytes (RBC)
May bind both endogenous and exogenous compounds.
Consist of about 45 % of the volume of the blood.

METHODS FOR STUDYING DRUG-PROTEIN BINDING

Equilibrium dialysis
Dynamic dialysis
Diafiltration
Ultrafiltration
Gel chromatography
Spectrophotometry
Electrophoresis
Optical rotatory dispersion and circulatory dichroism

Drug-protein binding is influenced by a number of important factors:

1. The drug Physicochemical properties of the drug. Total concentration of the drug in the body
2. The protein Quantity of protein available for drug-protein binding. Quantity or physicochemical
nature of the protein synthesized.
3. The affinity between drug and protein, including the magnitude of the association constant.
4. Drug interactions competition for the drug by other substances at a protein-binding sites. Alteration
of the protein by a substance that modifies the affinity of the drug for the protein.
5. The pathophysiologic condition of the patient.

Plasma drug concentrations are generally reported as the total drug concentration in the plasma, including
both protein-bound drug and unbound drug concentrations.

CLINICAL SIGNIFICANCE OF DRUG-PROTEIN BINDING

The plasma protein concentration is controlled by a number of variables including:

1. protein synthesis
2. protein catabolism
3. Distribution of albumin between intravascular and extravascular space.
4. Excessive elimination of plasma protein, particularly albumin.
Metabolism serves three principal purposes:
(1) to supply energy for body functions and maintenance;
(2) to break down ingested (foreign) compounds, i.e., catabolism, to simpler structures, and
biosynthesis of more complex molecules, i.e., anabolism, usually requiring energy; and
(3) For the conversion or biotransformation of foreign compounds to more polar, water-soluble and
ionized structures which can be eliminated more easily.
 Drug metabolism refers solely to the chemical biotransformation of a drug by the biological
environment.
Drug metabolism is often termed detoxication or detoxification, which indicates one of the main
functions of metabolism, namely, the formation of more polar and water-soluble compounds resulting
in reduction of their pharmacological activity and more rapid excretion from the body.
The term detoxication or detoxification should not be used as a collective term for drug metabolism
because the metabolic products of some drugs are even more toxic or more pharmacologically active
than parent molecules.
The metabolism of phenacetin, pyridine, sulfadiazine and sulfamerazine results in more toxic metabolic
products; analogs of purines and pyrimidines form carcinostatics; Prontosil forms sulfanilamide;
imipramine forms desmethylimipramine; and -methyldopa forms -methylimipramine metabolites
of enhanced pharmacological activity.
Drug metabolism is very complex. Usually drug metabolites are more water-soluble than the parent
structure because the derivatives contain more functional groups, or they are conjugated with
hydrophilic substances.
Metabolites are usually more water-soluble there are many exceptions. For example, some metabolites,
which are less water-soluble than the parent compounds are p- chlorophenaceturic acid, a metabolite
of p- chlorophenylacetic acid; m-acetonamidobenzoic acid, produced from m-aminobenzoic acid; and
N-acetyl-sulfanilamide, a metabolite of sulfanilamide.
The metabolites are usually not concentrated in the biological fluid to the limit of their water-solubility
because they are excreted before reaching saturation.
Mostly, drug metabolites are more ionized at physiological pH than their parent structures and are,
therefore in the form of water-soluble salts which have reduced lipid solubility.
Acidic metabolites are often excreted from the body by active secretion in the renal tubule.

Pathways of Drug Metabolism

The principal site of drug metabolism is the liver; less important are the kidney, muscle tissue and gut
wall.
Metabolizing enzymes occur in the soluble, the mitochondrial, or the microsomal fractions. However,
metabolism can also take place in the bloodstream to some extent because some enzymes produced
by the cell spill over into the extracellular fluid.
Drug metabolism reactions are divided into Phase 1, or non-synthetic reactions, and Phase 2, or
synthetic reactions.
The most common drug metabolism reactions comprise oxidation, reduction, hydrolysis, and
conjugation. Often a drug is metabolized simultaneously competing reactions.
The extent of formation of the different metabolites depends on the relative rates of reaction.
Additionally, many drugs are subjected to different metabolic reactions, consequentially, where
oxidation, reduction or hydrolysis reactions are followed by conjugation.
Microsomal enzymes requiring oxygen and NADPH (nicotinamide-adenine-dinucleotide-phosphate)
catalyze most of the oxidation reactions.
The present knowledge on drug metabolism allows a fairly accurate prediction of metabolic pathways
for a given compound. The formation of double conjugates is rare because a compound, once
conjugated, is easily excreted.

Red Blood Cells in Drug Metabolism

The principal function of erythrocytes (RBC) is to exchange oxygen for carbon dioxide at the tissue
level.
RBCs are equipped with numerous enzyme systems whose functions are energy supply for the cell
protection of hemoglobin and cell membrane from oxidation. Since the RBC has no nucleus, no
mitochondria, no ribosomes or m-RNA, it cannot synthesize protein. Having no cytochrome P-450, it
was assumed that the RBC is metabolically inert, hence may serve as carrier for drug targeting.
 However, evidence suggests that a number of enzymes present in the RBC indeed metabolize drugs,
such as aspirin, dopamine, epinephrine, esmolol etc.

Glucuronic Acid Conjugation

Glucuronidation is a condensation of the drug or its primary metabolite with d-glucoronic acid. The
reaction requires activation of glucoronic acid by synthesis of UDPGA (uridine diphosphate glucoronic
acid). All glucoronides have a free carboxyl group.
UDPGA is formed from UDP-glucose by a dehydrogenase found in the supernatant fraction of the liver.
The reaction between UDPGA and the drug is catalyzed by glucoronyl transferase, a solubilized
microsomal enzyme found in the liver, kidney, GI tract and skin.
Alcohols and phenols from ether type glucuronides; aromatic and aliphatic carboxylic acids form ester
type glucuronides.
Glucuronides are more water-soluble than the parent structures due to the large hydrophilic
carbohydrate moiety, thus reducing the lipid/water partition coefficient.
Glucuronides are usually more acidic than the parent molecule hence are more ionized at physiological
pH. They can. Therefore, less easily permeate through membranes and are poorly reabsorbed by the
kidney tubuli.
Drug glucuronides may be hydrolyzed by -glucuronides found in lysosomes.
Glucuronides are often excreted by tubular secretion.
Tubular secretion and glomerular filtration eliminate Glucuronides of menthol, phenol and resorcinol.
But glucuronides may also be excreted via the bile. Upon biliary excretion the glucuronides may be
hydrolyzed in the gut by -glucuronides produce by E. coli and nonspore forming anarobes, bacteroides
and fidobacterium and lactobacilli.
Diethylstilbestrol, morphine, gluthimide and chloramphenicol are excreted into feces without biliary
recycling.
In man there seem to be no sex differences in glucouronidation as are found in animals such as the
rat.
Microsomal drug inducers increase the activity of glucoronyl transferase, whereas microsomal enzyme
inhibitors and some drugs reduce or inhibit glucoronyl transferase activity.
During pregnancy, glucuronidation is reduced probably due to increase progesterone and pregnanediol
levels.
Newborns have a very low glucuronyl transferase activity. This is cause of the Gray syndrome in
newborns treated with chloramphenicol; kernicterus results from inability to conjugate bilirubin.
Drugs that compete for glucuronidation or reduce the already low glucuronyl transferase activity can
precipitate Kernicterus. Administration of Phenobarbital to the newborn or the mother before delivery
increases the rate of formation of glucuronyl transferase by enzyme induction, hence reduces the free
bilirubin level by conjugation.

Sulfate Conjugation

In sulfate conjugation, sulfate is converted to APS (adenosine-5-phosphosulfate) and further to PAPS

(3-phospho-adenosine-5-phosphosulfate) utilizing ATP.
PAPS transfer the sulfate to the drug molecule in the soluble fraction of the cell.
Several sulfotransferases or sulfokinases exist; some are found in the liver, kidney and GI tract, such
as those for the sulfate conjugation of phenol.
The sulfate pool in the organism is limited and easily depleted. Therefore, with increasing drug doses
sulfate conjugation becomes easily saturated and, hence, proceeds at zero order.
The limited availability of sulfate is probably the reason that glucuronic acid conjugation increases over
sulfate conjugation with increased dose size.
The human newborn is already capable of sulfate conjugation but this pathway becomes easily
saturated due to limited sulfate pool.
Glycine Conjugation

Glycine is the most common endogenous amine for conjugation with organic acids, such as aromatic
heterocyclic carboxylic acid drugs and aliphatic acids, especially those with aromatic substituents.
However, most of the non-substituted aliphatic acids are too rapidly oxidized to be conjugated.
Glycine conjugation takes place usually in the mitochondrial fraction. However, bile acids are
conjugated with glycine in the microsomal fraction.
The glycine pool in the body is limited, hence increased dose size result in zero order kinetics of
formation of hippuric acid.
The conversion of hippuric acid to an active form involves Coenzyme A.
Glycine conjugation in man is reduced in liver damage.
The formation of hippuric acid upon administration of benzoic acid is used as a liver function test.
Newborns and aged have a reduced glycine pool.

Glutamine Conjugation

Glutamine is available in man for conjugation with organic acids, such as phenylacetic and related
acids.
An acylating enzyme for glutamine conjugation is localized in the liver and kidney.

Acetylation

Conjugation by acetylation of aromatic primary amines, aliphatic amines, amino acids, hydrazines,
hydrazides and sulfonamides occurs in many tissues. The latter ones from N 1 and N4 acetyl derivatives.
Secondary amines are not acetylated. Usually acetylation is a minor pathway of metabolism except for
isoniazid and sulfonamides. Acetylation occurs in reticuloendothelial cells of the liver, lung, spleen and
mucosa.
The newborn is not capable of acetylation. There exist different acetyl transferases in man.
The presence of the various acetyl transferases is genetically determined (slow acetylation and fast
acetylators). Particularly the presence of acetyl transferase for acetylators of isoniazid shows racial
distribution. However, slow acetylators for isoniazid show a rate of acetylation of sulfanilamide identical
to that of the fast acetylators of isoniazid.

Methylation

Methylation, although a minor pathway of metabolism, is of importance for many endogenous

substances.
In methylation first S-adenosylmethionine is formed which reacts with the drug in the presence of a
methyl transferase.
Methylation may occur in different tissues, such as liver, brain, kidney, skin, blood cells, glands, nerve
fibers and lung. Usually methyl transferases are found in the supernatant fraction; for cathecols and
phenols they are found in the microsomal fraction.

Enzyme Induction

The intensity and duration of pharmacological effect of drugs depend largely on their rate of metabolism
and excretion. May drugs, such as barbiturates, and other chemicals, such as the insecticides DDT and
chlordane, may alter the enzyme activity in liver microsomes resulting in a faster rate of metabolism.
This is called enzyme induction.
A drug that stimulates its own metabolism the phenomenon is called auto-induction. Since most of the
metabolic reactions are not specific for only one drug but serve as pathways for the metabolism of
many compounds having some common characteristics, one enzyme inducer may therefore stimulate
the rate of metabolism of another drug. This is termed foreign-induction. If the drug so stimulated in
 its metabolism were given alone, it would not necessarily result in enzyme induction. A few examples
may clarify this complex situation. If Phenobarbital is given repeatedly its metabolism is increased
(auto-induction). If a dose of hexobarbital is then given its metabolism is also increased (foreign-
induction). The same would happen if hexobarbital are stimulated in their metabolism by auto- and
foreign- induction (cross-induction).
The anticoagulant warfarin does not stimulate its own metabolism not even during prolonged therapy.
However, its metabolism is stimulated by concomitant administration of Phenobarbital (foreign-
induction).
Enzyme induction is not a disease; it is an adaptation of the body to exogenous material.
Enzyme induction does not proceed indefinitely but levels off reaching maximum stimulation that occurs
in a period of from several days to several weeks.
The rate of enzyme induction is usually to be dose dependent. Enzyme induction persists as long as
the enzyme inducer is administered. Upon termination of administration of an enzyme inducer, the rate
of metabolism returns to its normal level within a period of 10-30 days. In some cases it is associated
with an increase in synthesis of protein. In these cases the endoplasmic reticulum is multiplied and
liver weight increases. However, the number of liver cells is not increased, only the size of the cells is
enlarged.
In other cases the endoplasmic reticulum is not changed and cell size and liver weight remain
unchanged. It is believed that in these cases the level of activity is increased.

Enzyme Inhibition

In enzyme inhibition drugs compete with each other, even those structurally unrelated, for the
pathways of their metabolism.
This results in the inhibition of biotransformation and inactivation of these drugs. Consequently their
pharmacological effect is increased and prolonged. Pharmacokinetically, the overall elimination rate
constant is reduced due to diminished metabolism while peak level rise.
Possible mechanisms of enzyme inhibition are either competition for identical pathways of
biotransformation, or reduction in enzyme activity. Again, enzyme inhibition persists only as long as
the inhibiting drug is given. Upon withdrawal of the inhibiting drug, rates of metabolism return to their
normal pre-inhibition levels.

First-Pass Effect

Drugs may metabolize in the gastrointestinal epithelium during absorption, or by the liver before they
reach systemic circulation. This latter process is called the first-pass effect and reduces the systemic
availability of the drug. The first-pass effect is also one of the explanation half-life of some drugs when
given I.V. and P.O. It also explains quantitative and qualitative differences in the metabolism of one
and the same drug following both I.V. and P.O. administration.
The importance of the first-pass effect depends on the metabolic capacity for the particular drug, rate
of metabolism and rate of absorption. If the amount of drug administered is small, but capacity and
rate of metabolism are high, a large fraction of the drug may be metabolized, reducing the extent of
bioavailability. With increasing dose sizes first-pass metabolism may become saturated, thus increasing
the extent of bioavailability.

DRUG EXCRETION

Drug excretion is the removal of the intact drug. Nonvolatile drugs are excreted mainly by renal
excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the
urine. Other pathways for drug excretion may include the excretion of drug into bile, sweat, saliva, milk
(via lactation), or other body fluids.
 Volatile drugs such as gaseous anesthetics, or drugs with high volatility, are excreted via the lungs into
expired air.
Drug elimination in the body involves many complex rate processes. It is described in terms of
clearance.
The term clearance describes the process of drug elimination from the body or from a single organ
without identifying the individual processes involved.
Clearance may be defined as the volume of fluid cleared of drug from the body per unit of time. The
units for clearance are mL/min or L/hr.
The volume concept is simple and convenient, because all drugs are dissolved and distributed in the
fluids of the body.
The advantage of the clearance approach is that it applies to all elimination rate process.

The Kidney
The kidney is the main excretory organ for the removal of metabolic waste products and plays a major
role in maintaining the normal fluid volume and composition in the body.
To maintain salt and water balance, the kidney excretes electrolytes, water, and waste products while
conserving solutes necessary for proper body function.
The kidney has two endocrine functions:
(1) the secretion of rennin, which regulates blood pressure; and
(2) Secretion of erythropoietin, which stimulates red blood cell production.

Regulation of Renal Blood flow

Blood flow to an organ is directly proportional to the arteriovenous pressure difference (perfusion
pressure) across the vascular bed and indirectly proportional to the vascular resistance.
The normal renal arterial pressure is approximately 100 mm Hg and falls to approximately 45 to 60
mm Hg in the glomerulus (glomerular capillary hydrostatic pressure).
The pressure difference is probably due to the increasing vasculature resistance provided by the small
diameters pf capillary network. Thus, the GFR is controlled by changes in the glomerular capillary
hydrostatic pressure.
In the normal kidney, RBF and the GFR remain relatively constant even with large differences in mean
systemic blood pressure.
The term auto-regulation refers to the maintenance of a constant blood flow in the presence of
relatively constant blood flow, the filtration fraction (GFR/RPF) also remains fairly constant in this
pressure range.

Glomerular Filtration (GFR) and Urine formation

A normal adult male subject has a GFR of approximately 125 mL/min. About 180 liters of fluid per day
are filtered through the kidneys. In spite of this large filtration volume, the average urine is 1 to 1.5 L.
Up to 99% of the fluid volume filtered at the glomerulus is reabsorbed. Besides fluid regulation, the
kidney also regulates the retention or excretion of various solutes and electrolytes.
With the exception of proteins and protein-bound substances, most small molecules are filtered through
the glomerulus from the plasma. The filtrate contains some ions, glucose, and essential nutrients as
well as waste products such as urea, phosphate, sulfate, and other substances.
The essential nutrients and water are reabsorbed to various sites including the proximal tubule, loops
of Henle, and distal tubules. Both active reabsorption and secretion mechanisms are involved.
The urine volume is reduced, and the urine generally contains a high concentration of metabolic waste
and eliminated drug products.
Renal Drug Excretion
Renal excretion is a major route of elimination for many drugs.
Drugs that are nonvolatile, water soluble, have a low molecular weight, or are slowly biotransformed
by the liver will be eliminated by renal excretion.
The processes by which a drug is excreted via the kidneys may include any combination of the
following:
Glomerular filtration
Active tubular secretion
Tubular reabsorption

Glomerular filtration is a unidirectional process that occurs for most small molecules (MW<500),
including undissociated (unionized) and dissociated (ionized) drugs.
Protein bound drugs behave as large molecules and do not get filtered at the glomerulus. The major
driving force for glomerular filtration is the hydrostatic pressure within the glomerular capillaries.
The kidneys receive a large blood supply (approximately 25% of the cardiac output) via the renal
artery with very little decrease in the hydrostatic pressure.
Glomerular filtration rate (GFR) is measured by using a drug that is eliminated by filtration only (ie. It
is neither reabsorbed nor secreted). Examples of such drugs are inulin and creatinine. Therefore, the
clearance of inulin will be equal to the GFR, which is equal to 125 to 130 mL/ min. the value for the
GFR correlates fairly well with body surface area.
Glomerular filtration of drugs is directly related to the free or nonprotein-bound drug concentration in
the plasma.
As the free drug concentration in the plasma increases, the glomerular filtration for the drug will
increase proportionately.
Active renal secretion is an active transport process. As such, active renal secretion is a carrier-mediated
system that requires energy input, because the drug is transported against a concentration gradient.
The carrier system is capacity limited and may be saturated. Drugs with similar structures may compete
for the same carrier system. Two active renal secretion systems have identified systems for weak acids
and (2) weak bases. For example, probenecid secretion rate is dependent on renal plasma flow. Drugs
commonly used to measure active tubular secretion-hippuric acid (PAH) and iodopyracet (Diodrast).
These substances are both filtered by the glomeruli and secreted by the tubular cells.
Active secretion is extremely rapid and practically all the drug carried to the kidney is eliminated in a
single pass. The clearance for these drugs therefore reflects the effective renal plasma flow (ERPF),
which varies from 425 to 650 mL/min.
For a drug that is excreted solely by glomerular filtration, the elimination half-life may change markedly
in accordance with the binding affinity of the drug for plasma proteins.
In contrast, protein binding has very little effect on the elimination half-life of a drug excreted mostly
by active secretion. Because drug protein binding is reversible, the bound drug and free drug are
excreted by active secretion during the first pass through the kidney. For example, some of the
penicillins are extensively protein bound, but their elimination half-lives are short due to rapid
elimination by active secretion.
Tubular reabsorption occurs after the drug is filtered through the glomerulus and can be active or
passive. If a drug completely reabsorbed (eg. Glucose), then the values for the clearance of the drug
is approximately zero. For drugs that are partially reabsorbed, clearance values will be less than the
GFR of 125 to 130 mL/min.
The reabsorption of drugs that are acids or weak bases is influenced by the pH of the fluid in the renal
tubule (ie. Urine pH) and the pKa of the drug. of these factors together determine the percentage of
dissociated (ionized) and undissociated (nonionized) drug.
Generally, the undissociated species is more lipid soluble (less water soluble) and has a greater
membrane permeability.
The undissociated drug is easily reabsorbed from the renal tubule back into the body. This process of
drug reabsorption can significantly reduce the amount of drug excreted, depending on the pH of the
urinary fluid and the pKa of the drug.
 The pKa of the drug is a constant, but the normal urinary pH may vary from 4.5 to 8.0, depending on
diet, pathophysiology, and drug intake. Vegetable diets or diets rich in carbohydrates will result in
higher urinary pH, whereas diets rich in protein will result in lower urinary pH.
Drugs such as ascorbic acid and antacids such as sodium carbonate may alter urinary pH when
administered in large quantity.
Fluids administered intravenously cause by far the most important changes in urinary pH.
Intravenous fluids such as solutions of bicarbonate or ammonium chloride are used in acid-base
therapy. Excretion of these solutions may drastically change urinary pH and alter drug reabsorption.
The percentage of ionized weak acid drug corresponding to a given pH can be obtained from the
Henderson-Hasselbalch equation.

[Ionized]
pH = pKa + log ________________

[nonionized]
For a weak base drug, the Henderson-Hasselbalch equation is given as

[nonionized]
pH = pKa + log ________________

[ionized]

Drug Clearance

Drug clearance is pharmacokinetic term for describing drug elimination from the body without
identifying the mechanism of the process.
Drug clearance (body clearance, total body clearance, or ClT) considers the entire body as single drug-
eliminating system from which many unidentified elimination processes may occur. Instead of
describing drug elimination rate in terms of amount of drug removed per time unit, drug elimination
rate is described in terms of volume of fluid clear of drug per time unit.
These are several definitions of clearance, which are similarly based on volume.
The simplest concept of clearance regards the body as a space that contains a definite volume of body
fluid (apparent volume of distribution, VD) in which the drug is dissolved.
Drug clearance is defined as the fixed volume of fluid (containing the drug) cleared of drug per unit
of time.
The units for clearance are volume/time (eg, mL/min, L/hr). For example, if the Cl T of penicillin is
15mL/min in a patient and penicillin has a VD of 12 L, then from the clearance definition, 15 mL of the
12 L would be cleared of drug per minute.

Elimination rate (g/min)

ClT =
Plasma concentration (g/mL)