Biopharmaceutics

Dr Ghafourian
Aulton, M.E. Pharmaceutics The Science of Dosage Form Design (2001): Chap. 16-17 or chap.19-21 in 3rd edn (2007) 2. Williams, D. A., Foye, W.O., Lemke, T. L., Foye's Principles of Medicinal Chemistry (2002) 3. Shargel, L., Yu, A.B.C., Applied biopharmaceutics and pharmacokinetics (2004)
1.
1

Processes leading to biological activity

Pharmacodynamic Drug-receptor interaction properties Absorption Distribution Pharmacokinetic properties Metabolism (ADME properties) Excretion

Drug Absorption, Distribution, And Elimination

Drug at site of action
Intravenous Injection DISTRIBUTION ELIMINATION Unchanged drug excreted

ABSORPTION

BLOOD

Drug in site of administration

Bound drug

Unbound drug

Metabolism Metabolites excreted

DISTRIBUTION

Drug in tissues and other fluids

Biopharmaceutics
Biopharmaceutics is the study of factors which affect drug absorption, distribution, metabolism and excretion

Pharmacokinetics
Pharmacokinetics is the mathematical description of drug absorption, distribution, metabolism and excretion
4

Absorption and Fate

Oral, Transdermal, Intramascular, Nasal, Subcutaneous, sublingual, Absorption buccal, rectal

Pericardial, CNS, Placental Distribution transfer of drugs, etc Metabolism

Elimination

Disposition

Hepatic Renal

Excretion

others

Factors Affecting Drug Absorption and Fate

Physico-chemical Factors Physiological Factors Formulation Factors

Physicochemical Factors influencing Drug Absorption and Fate

Physico-Chemical Properties? Examples:

Solubility Surface activity Partition coefficient Degree of ionisation Intermolecular forces Distance between functional groups Stereochemistry Dipole moment Molecular weight and volume
H HO

CH3

OH

Drug Absorption
Absorption is passage of drug (in molecular form) from site of administration into blood circulation

80% of all drugs are solids Dissolution is essential before membrane transport
Step 2: Membrane permeation

Drug in formulation

Step 1: Dissolution

Drug in solution

Blood

Dissolution

Saturated layer around drug particle: diffusion layer Dissolution rate depends on the rate of diffusion of drug molecules from this layer: Noyes-Whitney equation

Drug particle

DA(CS C ) dC / dt h

Diffusion layer

dC/dt : Dissolution rate h: Thickness of diffusion boundary layer D: Diffusion coefficient C: Concentration of compound in medium at time t Cs : Solubility of compound in medium A: Surface area available for dissolution

Dissolution rate

Surface area (particle size, wettability, surfactants, bile) Solubility in diffusion layer (CS: crystal structure, solubilization by other excipients, pH of GI, hydrophobicity, bile, food) Amount of drug already dissolved (C, permeability) Diffusivity of drug (molecular size of drug, viscosity of luminal contents) Boundary layer thickness (motility patterns of GI) Volume of solvent available (Co-administered food and fluids)
Drug particle

Diffusion10layer

Dissolution rates of solids in liquids

MSCL: read pages 18-22 (chapter 2) Aultons Pharmaceutics, 3rd edition, 2007

11

Absorption: membrane transport

involves crossing several layers of cells in different body tissues, e.g. cells of gastrointestinal tract, cells of blood vessels Membrane transport is also necessary for distribution in tissues, metabolism and excretion

Through gaps between cells (Paracellular) Through the cell membrane (transcellular)

12

Absorption:
Mechanisms of transcellular transport

Diffusion through hydrophilic pores (possible only for very small and polar molecules) Carrier mediated transport (specific, saturable) Diffusion through lipid of cell membrane (phospholipids)
13

Absorption:
Passive Transport (through lipid membranes)
The rate of transport of drug across the membrane can be described by Fick's first law of diffusion:
Small intestine has larger area: more absorption

Partition coefficient: affinity to the membrane

Diffusion coeff in the membrane

Thickness of the membrane

As blood carries the drug quickly, it becomes diluted by blood volume and distribution and PB. So it is a sink and, Ch>>Cl:

First order

14

Absorption:
Passage through lipid membranes

For a drug to cross a membrane barrier it must normally be soluble in the lipid material of the membrane to get into membrane, also it has to be soluble in the aqueous phase as well to get out of the membrane. What physico-chemical property measures affinity to water or to lipid?

Drug in formulation
Dissolution

Drug in solution
LIPID AQUEOUS LIPID AQUEOUS LIPID

Blood

15

Compare diffusion rates

Which will dissolve best in oil and in water? How do we measure this in vitro?

procaine

tocainide

16

Partition coefficient

Oil

Water

Oil Water

Hexane:CH3CH2CH2CH2CH2CH3

Immiscible solvents
17

?
O

Oil Water

+
OH

OH

Salicylic acid
Immiscible solvents
18

Partitioning

Solute in oil Solute in water

Equilibrium
19

Solute in oil

At Equilibrium state:
Solute in water

k (transfer from oil to water) = k (transfer from water to oil) Concentrations will remain constant

What determines the concentrations?

20

Like dissolves like NaCl

Hydrophilic groups: OH NH2 COOH Ionised groups

Lipophilic groups: Hydrocarbon chains and rings Aromatic rings Large halogen atoms (Cl, Br, I)

21

Some examples:
OH CH3

Cl

CH3

22

Partition Coefficient

Distribution of the solute between two immiscible phases will lead to an equilibrium state At equilibrium the rate of transfer of solute between two phases are the same. The equilibrium constant is known as partition coefficient (K or P):

Solute in oil

P or K =Coil/Cwater
Solute in water
23

Relationship between Absorption Rate and P

Rate of absorption

For most drugs log P is smaller than the optimum and a linear relationship is observed:

Rate of absorption hexethal

Log P

secobarbital pentobarbital phenobarbital barbital 0 1 2 3 Log P

24

Ionisation and Absorption

Ionised species will not be absorbed:

Cl HN HO O Cl O
-

Cl HN O Cl

+H

25

pH - Partition Theory for Absorption

The gastrointestinal and other biologic membranes act like lipid barriers The un-ionised form of the acidic or basic drug is preferentially absorbed Most drugs are absorbed by passive diffusion The rate of drug absorption and the amount of drug absorbed are related to its oil-water partition coefficient; the more lipophilic the drug, the faster its absorption Weak acidic and neutral drugs may be absorbed from the stomach, but basic drugs may not
26

Ionisation and pH at Absorption site

Most drugs are weak acids or weak bases Only the fraction of drug that is un-ionised passes through lipid membranes (the weaker the acid or base is the higher fractions of the drug will exist in un-ionised forms at any pH value) The proportion un-ionised depends on pH value of the medium and pKa of acids and bases (can be calculated through Henderson-Hasselbalch equation)

The dissociation constant (pKa), partition coefficient (log P) and pH of the fluid at the absorption site determine the extent of absorption from a solution
27

Fraction of un-ionised drug

For Acids : RCOOH H RCOO [ H ].[ RCOO ] Ka [ RCOOH ]
Acids

with higher pKa values are weaker acids meaning that they are mostly un-ionised and therefore they pass through the biological membranes more easily

[ionised] pH pKa log [un ionised]

28

Fraction of un-ionised drug

For Bases : RNH 3 RNH 2 H [ RNH 2 ].[ H ] Ka [ RNH 3 ]
Bases with higher pKa values are stronger bases

(higher ionised fractions) and therefore they pass more slowly through the membranes

[ionised] pKa pH log [un ionised]

29

pH values of different body compartments

Stomach pH 1-3 Duodenum pH 5-6 Increasing gradually in jejunum Ileum pH 7-8 Blood pH 7.4 pKa of a weak acid = 4.5
Stomach

pH = 2
(0.3%) [RCOO-]

membrane

Blood circulation

pH = 7.4
[RCOO-] (99.87%)

(99.7%) [RCOOH]

[RCOOH] (0.13%)
30

Percent of Drug Existing in Ionised Form

100 Ionised% for acids pKa pH 1 10 100 ionised% for bases pH pKa 1 10 Un ionised% 100 ionised%

31

Example 1
O

OH

OH

Its an acid pKa = 3.0 Percent absorbed at pH 1 = 61 Percent absorbed at pH 8 = 13

Salicyclic acid (Antiinflammatory)

32

Example 2
O H3C H3C N H N SH

CH3

Thiopental

It is an acid (anesthetic, anticonvulsant) pKa = 7.6 Percent absorbed at pH 1 = 46 Percent absorbed at pH 8 = 34

33

Example 3
CH2 HO CH3 H O N

It is a base pKa = 8.4 Percent absorbed at pH 1 = 0 Percent absorbed at pH 8 = 18

Quinine (Antimalarial)

34

Example 4
CH3

It is a base pKa = 9.2 Percent absorbed at pH 1 = 0 Percent absorbed at pH 8 = 16

H N CH3

Dextromethorphan (antitussive)
35

Question

Why some drugs are designed to contain a quaternary ammonium group?

CH3 N N H3C
Cl
-

H3C N
+

H3C

CH3

Pyrvinium chloride (anthilmintic)

36

More on Partition Coefficient

Some drugs may be poorly absorbed after oral administration even though they are available predominantly in an un-ionised form in GI. This is mainly due to the low lipid solubility Polar or hydrophilic molecules such as gentamicin are poorly absorbed after oral administration and must therefore be administered parentrally The selection of a compound with higher partition coefficient from a series of research compounds provides improved pharmacological activity
37

Ion pair transport

For example quaternary ammonium compounds :

COO-

N+ COO- N+
38

Absorption: Carrier mediated

The body has a number of specialized mechanisms for transporting particular compounds; for example, glucose and amino acids. Sometimes drugs can participate in this process; e.g. 5-fluorouracil, cephalexin, amoxycillin

Active
Facilitated
39

Absorption: Carrier mediated

Active transport requires energy Can proceed against a concentration gradient Structural specificity Competitive inhibition is possible The process can be saturated: Higher doses have lower bioavailability

e.g. Vitamin transporters, sugar transporters, bile acid transporters If a drug structurally resembles the vitamins or other metabolites will be able to be transported by these

40

Absorption rate in active transport

Michaelis Menten equation

Absorption rate : dC Vmax C dt km C

k m C dC Vmax C dt km dC kC dt

C k m dC Vmax dt dC k0 dt

41

Facilitated transport

no transport against a concentration gradient only downhill but faster A drug carrier is required but no energy is necessary. e.g. vitamin B12 transport Structural specificity Competitive inhibition is possible Site specificity Saturable if not enough carrier
42

Pinocytosis (a type of endocytosis)

Plasma membrane invaginates Invaginations become pinched off Membrane-bound vesicles in the cell Material transferred to other vesicles or lysosomes and digested Important for macromolecules

For example Vitamin A, D, E, and K

43

Factors Affecting Drug Absorption and Fate

Physico-chemical

Factors Physiological Factors Formulation Factors

44

Physiological Factors

45

Physiological Factors Affecting Oral Absorption

Gastric and intestinal motility and transit time Physiological Surface of absorption sites Gastrointestinal fluids (Viscosity, Volume, pH, Mucin, Bile salts) Degradation in gastrointestinal fluids Portal vein flow rate First pass metabolism Food Others (Age, Sex, Disease)
46

 It is not an absorption organ since there is a relatively small

surface area (1 m2). Gastric emptying half-time is too short (about 30 min). The stomach is lined with a thick mucus covered membrane (50mg/ml, 400 m versus 20mg/ml, 200 m for the small intestine). Permeability of gastric membrane is too low. Carriers exist in small intestine only.

Absorption in stomach?

47

Transit of pharmaceuticals in Gastrointestinal tract: Stomach

Little drug absorption (low surface area) Gastric emptying (or residence) time is 5 min 2 hours Motility pattern is called Interdigestive myoelectric cycle (migrating myoelectric complex MMC): in fasting state
Phase III Phase IV

Pressure (mm Hg) 80 Phase II 40 Phase I

Phase I: 40-60 min, relatively inactive, rare contractions Phase II: 40-60 min, increasing number of contractions Phase III: powerful peristaltic contractions which open pylorus Phase IV: short transitional period
48

Cycle repeats itself every 2 hours until a meal is ingested

Stomach motility in fed state

There are no distinctive phases. The contraction has moderate strength Proximal stomach:

Relaxes to receive food Gradual contractions to move food distally

Distal stomach: peristaltic and cystolic contractions to achieve:

The diminution of the size, mixing and grinding Moving the food towards the pyloric sphincter

Pyloric sphincter allows liquid and small food particles to empty

49

50

Gastric emptying of pharmaceuticals

Fed state:

Liquids, pellets and disintegrated tablets empty with food Large sustained or controlled release dosage forms retained longer Stomach is less discriminatory between dosage forms Emptying time is related to the point in MMC at which drug is ingested
51

Fasted state:

Factors controlling Gastric emptying time of pharmaceuticals

Dosage form Fed/fasted state of the stomach: food delays gastric emptying Composition of the food: fatty foods delay gastric emptying Disease state (hyperthyroidism accelerates) Effect of drugs: metoclopramide (increase rate of emptying and drug absorption), anticholinergics (e.g. proprantheline) and tricyclic antidepressants (delay) Postural position (lying on your left side delays)
52

Small intestine transit

Propulsive and mixing movements Transit time determined by propulsive movements Transit time is important for bioavailability Transit time relatively constant at about 3 h Intestine does not discriminate between food types, solid/liquid, or fed/fasted state Transit time specially important for:

Controlled- or sustained-release systems Enteric coated dosage forms Low dissolution rate drugs Drugs with carrier mediated absorption
53

Colonic Transit

Transit time is long and variable (2-48 h): depends on the type of dosage form, diet, eating pattern and disease state Propulsive and segmental (to mix the luminal contents) movements

Segmental: mixing of luminal contents resulting in small movements due to contraction of the circular muscle Propulsive: Short bursts of activity followed by long periods of stasis (3-4 times daily) due to contractions of longitudinal muscle

Important for colon delivery systems that make use of bacterial enzymes e.g. reductases
Enzyme POLYMER N=N
54

e.g. sulphasalazine releases 5-ASA for inflammatory bowl diseases

Barriers to drug absorption

pH of stomach varies (1-3.5) increases in fed state (3-7) Chemical stability (penicillin, erythromycin), dissolution and permeability implications How? Luminal enzymes: pepsin (stomach), lipases, amylases and proteases (pancreas), esterases

Lumen:
Chemical degradation Enzymatic degradation Complexation e.g. tetracyclin Adsorption

Unstirred water Gastrointestinal layer membrane

Complexation to mucus (mucin) Water and mucus diffusion

Presystematic metabolism
Gutwall liver

Transcellular
Efflux Paracellular
55

Lumen

56

Gastrointestinal pH

Location Stomach Mid-distal duodenum

Jejunum Ileum

Fasted state pH 1 - 3.5 4.9 6.4

4.4 6.6 6.5 8.0

Fed state pH 3-7 5.2 5.1

5.2 6.2 6.8 8.0
57

Enzymatic and acidic hydrolysis

Acid hydrolysis: Penicillin G, Erythromycin, Digoxin, clorazepate

58

Effect of food

Gastric emptying time Complexation of drugs with components in diet e.g. tetracycline Alteration of pH: food acts as a buffer Simulation of GI secretions (enzymes and bile salts) Enzymes decompose susceptible drugs Bile salts are surfactants (increase wettability & solubility of some drugs e.g. griseofulvin) Bile salts form insoluble complexes with some drugs (e.g. neomycin) Competition between some drugs and nutrients for active absorption Increased viscosity of GI contents (reduce dissolution rate as well as diffusion) Some food change presystemic metabolism e.g. grapefruit juice inhibits cytochrome P450 increase bioavailability of terfenadine and cyclosporine Increased blood flow to GI and liver thus increased absorption rate and reduced first pass metabolism (increase bioavailability of suceptible drugs to 1st pass metabolism)
59

Biliary salts and and other physiological

surfactants
(Lysolecithin, Acid cholic, Taurocholate, ) Wettability and dissolution rate (Griseofulvin)

Insoluble complex (Neomycin, Kanamycin)

Mucin: Mucopolysaccharid (protectant)

An absorption barrier (tetracycline)
60

Formulation Factors Affecting Oral Absorption

Solutions:

effects of dilution in the stomach content?

(consider salt of a weak acid, or poorly soluble drug dissolved with the aid of cosolvents, surfactants,) Precipitation rate differs with the vehicles

Suspensions:

Dissolution rate limited Large surface area immediately created in stomach Bioavailability is controlled by particle size, crystal form, complexation with excipients, surfactant (wetting agent), viscosity
61

Formulation Factors Affecting Oral Absorption

Liquid-filled Capsules

Poorly water-soluble drugs may exhibit greater bioavailabilities from this formulations Release is affected by dissolution and splitting of the shell Non aqueous vehicles could be water immiscible or miscible (vegetable oils or PEG): Release results in dispersion with the help of emulsifiers and bile Drug ends up as emulsion, solution, fine suspension or nano/ microemulsion Drug has to partition out of the oil droplet or absorbed by fat absorption process (if digestible) Bioavailability is affected by solubility, particle size, vehicle (hydrophilic, lipophilic, digestible), surfactant, viscosity, complexation with excipients
62

Formulation Factors Affecting Oral Absorption

Powder filled capsules

Bioavailability better or the same as tablet Rapid dispersion after the release creates large surface area Dissolution rate of a capsule formulation depends on dissolution rate of shell, rate of water penetration into the encapsulated mass, rate of deaggregation of the mass, dissolution rate of dispersed particles Penetration of GI fluids into the mass depends on: Excipients (hydrophilic excipients increase penetration rate) Pack density (and porosity) of the mass Wettability of the drug (can be improved by surfactants) Bioavailability depends on particle size, use of salt form, crystal form, chemical stability of drug, nature and quantity of diluent, lubricant, wetting agent, and drug-excipient interactions, conditions of filling process, packing density, capsule shells 63

Formulation Factors Affecting Oral Absorption of Tablets

Disintegration is crucial: creating large surface area for dissolution Disintegration time depends on drug type and concentration, diluent, binder, disintegrant, lubricant and wetting agent as well as compaction pressure Two levels of disintegration Into granules Into small drug particles The overall bioavailability is controlled by Physicochemical properties of drug particle including wettability, surface area, crystal form, chemical stability The nature and quantity of excipients Drug excipient interactions Compaction pressure and speed Condition of storage and age of tablet
64

Enteric coated tablets

Resist low pH of stomach The coating polymers dissolve at PH 5 (small intestine) Significant delay in the onset of the therapeutic response Gastric emptying time is 5min several hours Emptying time (thus the onset of action) is less variable for individually enteric coated granules or pellets
65

Distribution

Drugs in bloodstream distribute throughout body fluids and tissues Like absorption, distribution also involves passage through the biological membranes (pH-partition theory governs the process) Other physico-chemical properties are also important in some of the distribution processes for example binding to plasma or body proteins
Sites of action
Kidney Neutral fat Muscles Blood Brain Other tissues Metabolism
66

Binding to plasma proteins Excretion

Distribution

Is drug able to cross membranes (lipophilicity, charge, pka)? What are the membrane properties in a given tissue?
Sites of action
Kidney Neutral fat Muscles Blood Brain Other tissues Metabolism
67

Binding to plasma proteins Excretion

Distribution

Those sites in the body that are not the drug target and distribution to which reduce the drug concentration at the target site are known as sites of loss Plasma protein binding Tissue depots (Neutral fat, well perfused tissues such as muscles) Metabolism Excretion Example: Imipramine (antidepressant)

Sites of action

Kidney

Neutral fat Muscles Blood Metabolism

Binding to plasma proteins Excretion

Brain
Other tissues
68

Protein Binding
P D P D complex [ P D] Ka [ P].[ D]

Specific intermolecular interactions are responsible:

Ion-ion interaction Hydrogen binding Van der Waals and hydrophobic interactions Concentration of free drug Distribution Drug half life Drug interaction (warfarin and phenylbutazone)
69

It has a big effect on:

Warfarin

Free Warfarin Phenylbutazone Albumin

Warfarin is normally 90% bound (10% free warfarin) Phenylbutazone is also binding to the same site: Taken together: 80% of warfarin is bound then 20% free warfarin: overdose

70

Drug distribution equilibria

Blood flow

The rate of movement depends on hydrostatic pressure in capillaries, physicochemical properties of drug, binding of drug to plasma and tissue proteins, the rate of blood flow Favourable concentration gradient Lipophilic, unionised molecules of MW<20,000 can diffuse easily Hydrophilic drugs have slower distribution rates; they diffuse from paracellular path with smaller molecules diffusing faster The amount of drug reaching a tissue may depend on the rate of blood flow or perfusion Perfusion rate is the highest in brain, kidney, liver and heart; drug distribution is fastest to these organs

Plasma proteins Drug Tissue proteins

71

Distribution rate

Drugs that cross capillary walls rapidly have perfusion controlled distribution (the distribution rate depends on how quickly new drug molecules are available for distribution): conditions changing blood flow will alter the distribution rate Permeability controlled distribution when capillary walls are poorly permeable to a drug In kidney, filtration is the mechanism of distribution: blood flow controls the hydrostatic pressure difference and therefore the filtration rate
72

Distribution in Kidney

fenestrated arterial glomerular capillaries (not large enough for blood cells and platelets) Higher hydrostatic pressure than rest of the body Filteration is dominant mechanism of distribution (x100-x400 faster distribution than other tissues) Plasma-protein bound drugs will not be filtrated (due to negative charge of proteins)

73

Distribution to the liver

Capillaries form sinusoids with discontinuous endothelium with large cavities Small solutes such as drugs can diffuse readily regardless of lipophilicity Sinusoids large enough for distribution of proteins and large molecules

74

75

Distribution to the Brain

Endothelial cells of the capillary wall are very closely packed with tight junctions A thin basement membrane, comprising lamin, fibronectin and other proteins, surrounds the endothelial cells and associated pericytes, and provides mechanical support and a barrier function Glial membrane made of cells called astrocytes cover the capillary wall Drug has to pass both layers

This

Blood-Brain Barrier (BBB) restricts distribution of drugs into brain Lipophilic drugs with log P of ~2 enter by passive diffusion Efflux pumps actively drive drugs such as chemotherapeutics from brain back into blood Brain tumours are unaffected by most chemotherapeutics

76

Distribution from mother to foetus

Maternal blood enters large cavities (sinuses) in placenta Finger-like projections from the foetus (villi) enter sinuses Villi is lined with epithelial cells and contain foetal capillaries: transport of drugs from the mother occurs through epithelial membrane of placenta and then endothelial membrane of foetal capillaries Placental membrane has very tight junctions: lipophilic drugs transport faster than hydrophilic; even hydrophilics are transported to some extent due to large surface area of villi Foetal blood has less plasma proteins thus higher concentration of free drug Foetal membranes not well developed thus easier 77 distribution into foetal tissues (such as brain)

Distribution into breast milk

Drug concentration in milk is related to maternal plasma conc. Milk-to-plasma drug concentration (M/P) ratio is often measured Passive diffusion M/P ratio is affected by composition of the milk and physicochemical properties of drugs

Plasma protein binding Lipophilicity pKa

Milk contains more lipid and less protein than plasma and is slightly more acidic Drugs concentrated in milk are: weak bases with low plasma protein binding and high lipophilicity
78

Volume of Distribution

A quantitative measure of distribution necessary to understand pharmacokinetics A 70 kg adult has:

12 L of extracellular water

0.04 L of plasma per kg of body weight 5 L of blood (3 L plasma, 2 L blood cells) 9 L interstitial fluid 28 L intracellular water

Upon iv injection, drug mixes with blood, equilibrates swiftly in plasma and transported throughout body Average cardiac output 4.8-6.4 L/min: distribution is complete very shortly after iv administration
79

Apparent Volume of Distribution

Drugs appear to distribute in the body as if it were a single compartment. The magnitude of drug distribution is given by the apparent volume of distribution (vd). Vd is the volume into which a drug appears to distribute with a concentration equal to its plasma concentration
Vd = Dose/C0

Determines the extent of distribution: a measure of the relative partitioning of drug between plasma (the central compartment) and the tissues Different Vd terms: Vdc, Vdss

For drug dosing decisions difference between these is not significant

Used to calculate the loading dose: Dose = Cp (target) x Vd

80

Apparent Volume of Distribution

Vd = Dose/C0 If drug distributes to a larger volume of body fluids, plasma concentration will be lower Macromolecular drug such as heparin cannot distribute out of capillaries: Vd is plasma volume (0.04 L/kg or 3 L) Polar small molecule compounds such as mannitol that does not bind to plasma proteins, can leave plasma and distribute into interstitial fluid; is not lipophilic enough to enter intracellular fluid: Vd is the volume of extracellular water (0.17 L/kg or 12 L) Lipophilic small molecule drugs (majority of drugs): can diffuse into cells; assuming no plasma or tissue protein binding, drug in extra- and intracellular fluids with similar concentrations: Vd close to volume of total body water (0.57 L/kg or 40 L): diazepam, phenytoin
81

Volume of Distribution: effect of protein binding

Determines the extent of distribution: a measure of the relative partitioning of drug between plasma (the central compartment) and the tissues partitioning across various membranes binding to tissue components binding to blood components (RBC, plasma protein) physiological volumes
binding to tissue components

Drug in blood

Drug in tissues
82

binding to blood components (RBC, plasma protein)

Effect of plasma protein binding

Drug-protein interaction is assumed to be reversible: Does it limit the drug distribution? (restrictive vs. nonrestrictive binding) Small Vd is not necessarily associated with a high plasma binding:
3

log Vd

-1

0.0

0.5

1.0

fu

Data taken from Obach et al 2008

83

Charge state in Vd models

Charge type Acids Median Vd

bases neutrals 2.3 1.1

Zwitterions 0.83

0.22

Differences in Vd of acids/bases may be due to different protein binding of acidic and basic drugs Albumin has two binding sites for drugs; both are positively charged, binding mainly anionic drugs (e.g. restrictive binding of NSAIDS) Basic lipophilic drugs such as antidepressants bind to albumin, AGP and lipoproteins (non-restrictive) Very lipophilic, water-insoluble compounds bind to lipoproteins Several models in the literature for basic and neutral molecules only (Lombardo et al 2002 and 2004)
84

Plot of Observed vs. Predicted

Acid Base

log Vd

-1

-2 -1 0

Calculated log Vd

85

Excretion

Kidney is the predominant organ of excretion

Normal blood flow (renal artery) 1.2 L/min (20% of cardiac output) Blood pass from the network of capillaries called glomerulus inside Bowmans capsule to enter a 2nd capillary network surrounding tubules Glomerulus is fenestrated allowing filtration of molecules below MW ~5000 Tubular reabsorption of (ion and water) and also lipophilic drugs Tubular secretion: removing certain molecules and ions (H+, K+) from blood into the filtrate in tubules
86

Renal Excretion of drugs

Glomerular filtration of non-protein bound drugs): filtrate will have drug concentration equal to unbound plasma concentration GFR (glomerular filtration rate) for each drug depends on its extent of protein binding: GFRdrug = fu.GFR Tubular reabsorption by passive transcellular diffusion due to higher concentration of drug in filtrate following water reabsorption (lipophilicity and pKa of drugs determines the extent of this) Tubular secretion of some drugs into filtrate (against conc gradient) via active transporters:

Transporters identified for organic cations, organic anions, neutral and cationic hydrophobic compounds but more common for ionised drugs They bind to free drug only, but protein-drug complexes can dissociate rapidly to make additional free drug: plasma-protein binding has little effect on this process Competitive drug interactions, e.g. penicillin and probencid for 87 acid transporter

Excretion by the Liver (Biliary excretion)

The liver secretes 0.25 to 1 liter of bile each day (stored in gallbladder and secreted into small intestine). Some drugs and their metabolites are excreted by the liver into bile Anions, cations, and non-ionized molecules containing both polar and lipophilic groups are excreted actively into the bile Molecular weight should be greater than ~ 300, optimally ~ 500 Some compounds are reabsorbed from intestine (enterohepatic recycling) if the physicochemical properties are appropriate Conjugates (phase II drug metabolites) e.g. glucuronides are often of sufficient molecular weight for biliary excretion, however they may break down by glucuronidases Drugs that are ionised intensively in the small intestine88 are excreted (cannot be reabsorbed)

Cp versus Time showing a Second Peak

89

Enterohepatic cycling

Enteroheptic Recycling

90

Excretion by other organs

Saliva Breast milk Sweat Expired air

91