Ciprofloxacin: Drug Metabolism and

Pharmacokinetic Profile
Mohammed A. Al-Omar
Department of Pharmaceutical Chemistry
College of Pharmacy, King Saud University
P.O. Box 2457, Riyadh-11451
Kingdom of Saudi Arabia

PROFILES OF DRUG SUBSTANCES, 209 Copyright ß 2004 Elsevier Inc.

EXCIPIENTS, AND RELATED All rights reserved
METHODOLOGY – VOLUME 31
DOI: 10.1016/S0000-0000(00)00000-0
210 M.A. AL-OMAR

CONTENTS

1. Uses, Applications, and Associated History . . . . . . . . . . . . . 210

2. Absorption and Bioavailability. . . . . . . . . . . . . . . . . . . . . . 211
3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
4. Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

1. USES, APPLICATIONS, AND ASSOCIATED HISTORY

Since 1980, many effective antimicrobial drugs of the synthetic
fluoroquinolone series have been developed for the treatment of bacterial
infections in humans. Ciprofloxacin is one of the most widely used drugs
of this group, and exhibits bactericidal effects by inhibition of DNA
gyrase [1]. The drug is structurally related to other quinolones, including
cinoxacin, enoxacin, lomefloxacin, nalidixic acid, norfloxacin, and
pefloxacin. This family of compounds contains a 4-quinolone nucleus
with a nitrogen at position-1, a carboxyl group at position-3, and
a ketone moiety at position-4. Ciprofloxacin is a fluoroquinolone
carboxylic acid, since it contains a fluorine atom at position-6, and
a carboxylic acid moiety at position-3 of the 4-quinolone nucleus.
Fluorinated quinolones have a wider spectrum of activity and more
potency as compared to non-fluorinated quinolone [2]. The piperazine
group at position-7 of the 4-quinolone nucleus is responsible for the
antipseudomonal activity of ciprofloxacin. The drug also contains a
cyclopropyl group at position-1, which enhances its antimicrobial
activity.

Ciprofloxacin is commercially available as the monohydrate phase of its

hydrochloride salt, and has been formulated for oral and ophthalmic
administration. The compound has also been developed as the lactate salt
for use in intravenous administration [3].

Ciprofloxacin is approved for use in the treatment of bone and joint

infections, infectious diarrhea caused by Shigella or Campylobacter,
lower respiratory tract infections, skin infections, and urinary tract
infections. It is the drug of choice for the treatment of infections caused
by Campylobacter jejuni. In addition, it has found off-label use as an
alternative drug for the treatment of gonorrhea, salmonella, and yersinia
 DRUG METABOLISM AND PHARMACOKINETIC PROFILE 211

infections [3, 4]. In general, ciprofloxacin is active against susceptible

gram-negative and gram-positive aerobic bacteria, so therefore it should
not be used alone for mixed aerobic–anaerobic bacterial infections [4, 5].

2. ABSORPTION AND BIOAVAILABILITY

All formulations of ciprofloxacin are rapidly and well absorbed from the
GI tract following oral administration, and the compound undergoes
minimal first-pass metabolism [3]. The presence of food in the GI tract
decreases the rate, but not the extent, of drug absorption. Antacids
containing magnesium, aluminum, and/or calcium, decrease the oral
bioavailability of ciprofloxacin [6]. The oral bioavailability of ciproflox-
acin is 50–85%, and peak serum concentrations of the drug are generally
attained within 0.5–2.3 h. Peak serum concentrations, and areas under
serum concentration-time curves (AUC), are slightly higher in geriatric
patients than in younger adults. In adults who receive a single 200 mg
dose of ciprofloxacin by intravenous (IV) injection over 10 min, serum
concentrations of the drug immediately following the injection average
6.3–6.5 mg/mL, and serum concentrations 1 and 2 h later average 0.87
and 0.1 mg/mL, respectively [4].

Ciprofloxacin is widely distributed into body tissues and fluids following

oral and IV administration. Highest concentrations of the drug generally
are found in bile, lung, kidney, liver, gall bladder, uterus, seminal fluid,
prostatic tissue and fluid, tonsils, endometrium, fallopian tubes, and
ovaries [4, 7, 8]. It also distributed into bone, aqueous humor, sputum,
saliva, nasal secretions, skin, muscle, adipose tissue, and cartilage [4, 7, 9].

The apparent volume of distribution of ciprofloxacin is 2–3.5 L/kg, and

the apparent volume of distribution at steady state is 1.7–2.7 L/kg. Only
low concentrations of ciprofloxacin are distributed into cerebrospinal
fluid (CSF). Peak CSF concentrations may be 6–10% of peak serum
concentrations. The drug is moderately bound to serum protein
(16–43%), and crosses the placenta and is produced with the mammary
milk [6, 10].

3. METABOLISM
At least four active metabolites have been identified, namely desethylene-
ciprofloxacin, sulfo-ciprofloxacin, oxo-ciprofloxacin, and N-acetyl-
ciprofloxacin. Oxo-ciprofloxacin appears to be the major urinary
metabolite, and sulfo-ciprofloxacin the primary fecal metabolite [4, 11].
212 M.A. AL-OMAR

Carolyn et al. have reported two additional ultraviolet-absorbing

metabolites in urine specimens [12]. The drug is partially metabolized in
the liver by modification of the piperazinyl group. Oxo-ciprofloxacin and
N-acetyl-ciprofloxacin microbial activities are comparable to norfloxacin,
and desethylene-ciprofloxacin is comparable to nalidixic acid for certain
organisms. About 40–50% of an oral dose is excreted unchanged in the
urine, and 15% as metabolites. Upto 70% of a parental dose may be
excreted unchanged, and 10% as metabolites within 24 h [13, 14].

Ciprofloxacin and its metabolite desethylene-ciprofloxacin were deter-

mined in human plasma using capillary electrophoresis in the presence of
N-(1-naphthyl) ethylenediamine dihydrochloride as an internal standard.
Krol et al. [15] have thoroughly investigated the biotransformation of
ciprofloxacin in body fluids using high performance liquid chromato-
graphy (HPLC) and proposed the sequence of metabolic pathways
illustrated in Figure 1.

4. EXCRETION
Ciprofloxacin is eliminated by renal and non-renal mechanisms. The
drug is partially metabolized in the liver by modification of the
piperazinyl group to atleast four metabolites. These metabolites, which
have been identified as desethylene-ciprofloxacin, sulfo-ciprofloxacin,
oxo-ciprofloxacin, and N-acetyl-ciprofloxacin, have microbiological
activities that are less than that of the parent drug, but may be similar
to or greater than that of some other quinolones [4, 8, 9].

Ciprofloxacin and its metabolites are excreted in urine by both

glomerular filtration and by tubular secretion. Following oral adminis-
tration of a single 250-, 500-, or 750-mg dose in adults with normal renal
function, 15–50% of the dose is excreted in urine as unchanged drug, and
10–15% as metabolites within 24 h. 20–40% of the dose is excreted in
feces as the unchanged drug and metabolites within 5 days [4, 5, 16, 17].
Most, but not all, of the unchanged ciprofloxacin in feces appears to
result from biliary excretion [4, 5].

Renal clearance of ciprofloxacin averages 300–479 mL/min in adults

with normal renal function, and the drug is 16–43% bound to serum
protein in vitro. It crosses the placenta and is distributed into the amniotic
fluid in humans. The usual human dosage has not revealed evidence of
harm to the fetus.
 DRUG METABOLISM AND PHARMACOKINETIC PROFILE 213

CH3
HN C N
H o
N N N
H

F COOH F COOH
O O
Desethylene-ciprofloxacin N-Accetyl-ciprofloxacin

HN
N N

F COOH
O
Ciprofloxacin

HO3S N HN
N N N N
O

F COOH F COOH
O O
Sulfo-ciprofloxacin Oxo-ciprofloxacin

Figure 1. Biotransformation of ciprofloxacin in body fluids, as proposed by

Krol et al. [15].

The drug is also distributed into human-milk [4, 5, 10]. In lactating

women who received 3 doses every 12 h of 750 mg of ciprofloxacin, the
concentration of the drug in milk that was obtained 2–4 h after a dose
averaged 2.26–3.79 mg/mL. Concentrations in milk were higher than
concomitant serum concentrations for up to 12 h after a dose [10]. The
plasma half-life is about 3.5–4.5 h, and there is an evidence of modest
accumulation [4].

5. REFERENCES
1. C.J. Gilles, R.A. Magonigle, W.T.R. Grinshaw, A.C. Tanner,
J.E. Risk, M.J. Lynch and J.R. Rice, J. Vet. Pharmacol. Therapy,
14, 400 (1991).
214 M.A. AL-OMAR

2. J.W. Spoo and J.E. Riviere, Veterinary Pharmacology and

Therapeutics, 7th edn., in H.R. Adams, ed., Iowa State
University Press, Ames, IA, p. 832 (1995).
3. Martindale, The Complete Drug Reference, 33rd edn., S.C.
Sweetman, ed., The Pharmaceutical Press, Chicago, p. 182
(2002).
4. Drug Information, 95th edn., G.K. McEvoy, ed., American
Society of Health-System Pharmacists, p. 493 (1995).
5. Thomson MICROMEDEX(R), Healthcare Series, Vol. 116,
DE0858 (2002).
6. R.L. Davis, J.R. Koup, J. Williams-Warren et al., Antimicrob.
Agents Chemotherapy, 28, 74 (1985).
7. W. Wingender, K.H. Graefe, W. Gau et al., Eur. J. Clin.
Microbiol., 3, 355 (1984).
8. M. Dan, N. Verbin, A. Gorea et al., Eur. J. Clin. Pharmacol., 32,
217 (1987).
9. D.C. Brittain, B.E. Scully, M.J. McElrath et al., J. Clin.
Pharmacol., 25, 82 (1985).
10. Drugs in Pregnancy and Lactation, 5th edn., G.G. Briggs,
R.K. Freeman, and S.J. Yaffe, Williams & Wilkins, Baltimore,
MD, p. 213 (1998).
11. H. Scholl, K. Schmidt and B. Weber, J. Chromatogr. Biomed.
Appl., 416, 321 (1987).
12. C.M. Myers and J.L. Blumer, J. Chromatogr. Biomed. Appl.,
422, 153 (1987).
13. M.A. Gonzalez, A.H. Moranchel, S. Duran et al., Clin.
Pharmacol. Therapy, 37, 633 (1985).
14. M.A. Gonzalez, A.H. Moranchel, S. Duran et al., Antimicrob.
Agents Chemotherapy, 28, 235 (1985).
15. G.J. Krol, G.W. Beck and T. Benham, J. Pharm. Biomed. Anal.,
14, 181 (1995).
16. K.H. Bannefeld, H. Stass and G. Blaschke, J. Chromatogr.
Biomed. Appl., 692, 453 (1997).
17. D. Paradis, F. Vallee, S. Allard et al., Antimicrob. Agents
Chemotherapy, 36, 2085 (1992).