COMPARISON OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PERINDOPRIL, CILAZAPRIL AND ENALAPRIL

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose).
2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h.
3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin-converting enzyme (ACE) activity in both acute and steady state studies.
4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat > cilazaprilat > enalaprilat.
5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses used.     

Steady-state pharmacokinetics and pharmacodynamics of cilazapril in the presence and absence of cyclopenthiazide.

Twenty-two patients with essential hypertension received a single dose of 2.5 mg cilazapril and were then randomised into a double-blind parallel group study to receive either placebo, 1.25 mg cilazapril + 0.5 mg cyclopenthiazide (CPTZ), 2.5 mg cilazapril + 0.5 mg CPTZ, or 2.5 mg cilazapril alone for 1 month. After oral administration of a single dose of 2.5 mg cilazapril, the active diacid cilazaprilat appeared rapidly in the plasma (Tmax 2.0 +/- 0.2 h). With the radioinhibitor assay used in this study, a single elimination phase of cilazaprilat was evident, with a half-life (t1/2) of 2-3 h. At steady state, the pharmacokinetics of cilazaprilat were similar to single-dose administration and were not altered by CPTZ. The Cmax and area under the curve (AUC) of cilazaprilat were directly proportional to dose. Cilazapril administration in the dose range of 1.25-2.5 mg produced a dose-proportional inhibition of angiotensin-converting enzyme (ACE) activity that was maximum 2 h after drug administration. The degree of ACE inhibition correlated with the plasma concentration-time profile of cilazaprilat and the maximum decrease in blood pressure (BP). The EC50 for ACE inhibition by cilazaprilat was 7.7 ng/ml after acute treatment and was not significantly altered during chronic administration or by concomitant administration of CPTZ. There was no evidence of a dose-related antihypertensive effect of cilazapril at steady state and, with the small numbers of subjects used in this study, there was no evidence of 24-h BP control with monotherapy.     

Pharmacokinetics of intravenous cilazaprilat in normal volunteers.

The pharmacokinetics of 1 mg, 2 mg and 4 mg of cilazaprilat administered intravenously were determined in a group of eight volunteers. The fall in plasma concentration was polyphasic. Elimination was predominantly by renal excretion of the unchanged drug. The mean renal clearance values following 1 mg, 2 mg and 4 mg doses were 5.3 +/- 0.5, 8.1 +/- 0.5, and 9.8 +/- 0.5 l h-1 and plasma clearances were 7.8 +/- 0.5, 10.4 +/- 0.5 and 11.8 +/- 0.6 l h-1, respectively. Thus, plasma and renal clearances were dose dependent. ACE inhibition was greater than 82% for the first 4 h and about 55% at 24 h, after all three doses. There were no significant haemodynamic effects at any dose.     

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function

1 The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function.
2 After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0±3.0, 11.1 ± 3.0, 8.7 ± 3.7 and 6.7 ± 2.1 l h^-1 (means ± s.d.) in patients with creatinine clearances (CL_cr) of > 100, 41-100, 21-40, and 8-20 ml min^-1, respectively.
3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CL_cr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CL_cr < 40ml min^-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups.
4 This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.     

Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers

Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t1/2).     

Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model

The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 healthy male volunteers. Single oral doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects, each of whom received two different doses. A 2-week interval was allowed between treatments. Plasma levels of cilazaprilat, the active form of cilazapril, were measured for up to 3 days after drug administration. Peak plasma levels and 24-h areas under the curve (AUCs) were almost directly proportional to dose, and the elimination half-life (t1/2) during the first 8 h after dosing was 1.5 h. From 24 h on, there was a prolonged terminal phase with a t1/2 of approximately 50 h, and there was only slight dose-dependency during this phase. These data suggest that the pharmacokinetics of cilazapril are nonlinear. A physiologically realistic model based on saturable binding to converting enzyme was developed to account both for the drug kinetics and for the relationship of the kinetics to the dynamics of plasma converting enzyme inhibition. A number of conclusions relevant to the therapeutic application of cilazapril in hypertension are drawn from the data and from the pharmacokinetic-pharmacodynamic model.     

A comparison of the pharmacokinetics and pharmacodynamics of cilazapril between Chinese and Caucasian healthy,normotensive volunteers

Methods: The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 12 Chinese and 13 Caucasian, healthy, normotensive volunteers on their normal diet. Cilazapril was given orally as a single 2.5 mg capsule. Plasma was sampled for assay of the active metabolite, cilazaprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE-activity. Plasma concentrations of the active drug were measured by radioimmunoassay. Blood pressure and heart rate were measured at regular intervals. Results: The pharmacokinetic parameters of cilazaprilat were similar in the two ethnic groups. No significant difference in plasma concentrations was found at any of the time points. However, the weight-adjusted plasma clearance was significantly higher in the Chinese group, which is compatible with their lower body weight. The effects on plasma hormones were also comparable, although there was a somewhat greater rise in PRA and greater fall in aldosterone levels in Chinese than in Caucasians. The effect of cilazapril on blood pressure and heart rate was greater than was previously reported in healthy volunteers. Systolic (SBP) and diastolic (DBP) blood pressure were significantly reduced in both groups, but there was a more prolonged reduction in DBP in Caucasians. In addition, heart rate (HR) was significantly increased from baseline from 5 h onwards in Chinese subjects and significantly higher in comparison with Caucasians at most time points from 1.5 h onwards. The pharmacokinetic parameters of cilazapril were essentially the same in healthy, normotensive Chinese and Caucasians. Cilazapril reduced blood pressure acutely in both groups, with good tolerance. The inhibition of ACE in relationship to time and the plasma concentrations of cilazaprilat were similar in the two groups, although the changes in PRA and aldosterone suggest an ethnic difference in the responses of the renin-angiotensin-aldosterone system. Received: 24 January 1995/Accepted in revised form: 18 September 1995     

The pharmacodynamics and dose-response relationships of the angiotensin converting enzyme inhibitor, cilazapril, in essential hypertension.

In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor. All doses similarly and significantly (P less than 0.05) reduced supine and erect blood pressure without increasing heart rate. The hypotensive effect was evident within 1 h, maintained for up to 8 h, with a maximal effect at 6 h. There was no discernible effect on blood pressure at 24 h after dosing. Plasma ACE activity was markedly inhibited to the same extent after all doses, with a peak inhibition of 94-96% at 2-3 h. At 24 h residual inhibition of ACE was 49-54%. Plasma renin activity increased in a dose-dependent manner with a peak at 6 h, and returned to baseline at 24 h. No correlation was found between the reduction in blood pressure and plasma renin activity, either at baseline or following cilazapril. There were no significant changes in plasma noradrenaline and the responses to upright posture and to dynamic exercise were preserved. There was no evidence of impaired exercise performance. Cilazapril is a potent ACE inhibitor with a rapid onset and a prolonged duration of action. These results suggest that peak ACE inhibition is achieved by 5 mg and that lower doses may be useful in clinical practice.     

Single and repeated dose kinetics of the hypnotic agent loprazolam in healthy volunteers

The pharmacokinetics of loprazolam have been studied in eight healthy male volunteers after single and repeated 2 mg oral doses taken at night, for eight nights. The absorption and disposition of unchanged drug (HPLC-GC assay) and receptor active benzodiazepine-type materials (radioreceptor assay) were examined after the first and eighth dose. Maximum levels of approximately 10 ng ml-1 (range 3.6 to 15.5 ng ml-1) were reached within about 2.5 h after dosing. The post-peak levels declined in a single exponential fashion with an overall mean +/- SD half-life of 7.06 +/- 1.98 h and total areas under the curve ranging from 35.9 to 189.0 ng ml-1 h. There were no statistical differences between the values for the first and eighth doses. There was no evidence to suggest that significant accumulation of parent drug or receptor active benzodiazepine-type materials had occurred, and it is concluded that the kinetics of loprazolam would allow repeated daily doses of 2 mg.     

Initial and steady state pharmacokinetics of cilazapril in congestive cardiac failure.

Twenty one patients with NYHA class II-III congestive heart failure received single ascending doses of 0.5, 1.25 and 2.5 mg cilazapril daily followed by the minimum effective dose for six weeks. Fifteen patients completed the study, but the data from only 11 were sufficiently complete for kinetic evaluation. The pharmacokinetics of the metabolite, cilazaprilat, after a single dose of 0.5 mg cilazapril were similar to previous observations in healthy volunteers at identical dosage. Repeat administration, however, led to greater accumulation than previously observed in volunteers at the higher dosages of 1.25 or 5 mg given for 8 days. Seven patients experienced adverse events. Four were severe, leading to withdrawal of the patients from the study, but only one event was related to cilazapril. Of the other three, one suffered a myocardial infarction and subsequently died due to worsening congestive heart failure. One other patient was withdrawn with two adverse events probably related to cilazapril. No other deaths occurred amongst the study population, and there were no significant abnormalities in haematology or blood chemistry.     

Cilazapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cardiovascular disease.

Cilazapril is an orally active angiotensin converting enzyme (ACE) inhibitor which lowers peripheral vascular resistance without affecting heart rate. Like enalapril and ramipril it is a prodrug, and is hydrolysed after absorption to cilazaprilat, which has a long terminal phase elimination half-life permitting once daily administration. Given once daily at doses between 2.5 and 5 mg, cilazapril reduces arterial blood pressure in patients with mild to moderate essential and renal hypertension. Patients who do not respond adequately to cilazapril monotherapy usually respond with the addition of a diuretic such as hydrochlorothiazide. Preliminary data suggest that cilazapril is of comparable antihypertensive efficacy to usual therapeutic dosages of hydrochlorothiazide, slow release propranolol, nitrendipine, captopril and enalapril. In small studies cilazapril has produced sustained beneficial haemodynamic effects in patients with congestive heart failure. Cilazapril has been well tolerated and exhibits tolerability typical of ACE inhibitors as a class, including their lack of detrimental effect on glucose or lipid metabolism. Cilazapril should provide an effective alternative in the treatment of hypertension and, if preliminary data are confirmed, in congestive heart failure.     

Pharmacokinetics of ticlopidine during chronic oral administration to healthy volunteers and its effects on antipyrine pharmacokinetics.

1. The pharmacokinetics of ticlopidine, a novel antithrombotic agent, have been investigated in 10 healthy volunteers dosed orally with the drug (250 mg 12 hourly for 21 days), to determine the basic pharmacokinetic parameters in humans, to investigate its accumulation during repeated administration, and to assess its effects on hepatic drug-metabolizing enzymes. 2. After the first dose, peak plasma concentrations (median 0.31, range 0.08-0.80 mg/l) were generally found at 2 h. The levels decreased rapidly to a median concentration of 0.087 mg/l by 4 h then declined to 0.022 (range less than 0.005-0.128) mg/l at 12 h after administration, with apparent half-lives of approx. 4 h. The median AUC value for this first dosage interval (AUC tau) was 0.97 (range 0.41-3.49) mg h l-1. 3. Pre-dose plasma concentrations indicated that steady state was reached after 5-10 days, and then remained essentially unchanged through to the end of the study. From 30 h after the final dose, drug levels declined exponentially with a median half-life of 28.8 (range less than or equal to 20-50) h. 4. Following the final dose, the median peak concentration and AUC tau were 0.99 (range 0.22-2.12) mg/l and 4.06 (range 0.90-15.2) mg h l-1 respectively. Based on AUC values, the mean accumulation factor +/- SD was 3.73 +/- 1.14. 5. The metabolic status of subjects was assessed by administration of single doses of antipyrine (700 mg orally) 7 days before the first dose of ticlopidine and 2 days after the final dose. Treatment with ticlopidine decreased antipyrine clearance, demonstrating that it inhibited drug-metabolizing enzymes. Significant correlations (r2 = 0.84, p less than 0.01) were found between the AUC values for ticlopidine and antipyrine, indicating that the interindividual variation in the pharmacokinetics of ticlopidine are explained by differences in metabolic clearance.     

Cilazapril and enalapril inhibit local angiotensin I conversion in human veins but lack direct venodilating properties

We studied the angiotensin-converting enzyme (ACE)-dependent and ACE-independent (direct) effects of two ACE inhibitors, cilazaprilat and enalaprilat, in 12 healthy human subjects. The dorsal hand vein compliance technique was used because venous constriction and relaxation, independent of reflex responses and systemic ACE inhibition, can be measured by local infusions of very small amounts of drugs. Angiotensin I (dose range 6-1,550 ng/min) was infused alone or coinfused with cilazaprilat or enalaprilat (dose range 7.8-3,900 ng/min). In separate experiments, cilazaprilat or enalaprilat (dose range 3.9-31 micrograms/min), or prostaglandin I2 (PGI2, dose range 0.13-32 ng/min) was infused into veins that had been submaximally preconstricted with phenylephrine. Angiotensin I caused a marked venoconstriction limited by rapid tachyphylaxis. At doses greater than 78 ng/min, cilazaprilat and enalaprilat completely inhibited angiotensin I-induced venoconstriction. This inhibition was reversible after 14-31 min, suggesting an inhibition of ACE associated with the vein wall. Infusions of cilazaprilat or enalaprilat had no effect on the diameter of the vein at rest or after submaximal preconstriction with phenylephrine. In contrast, exogenous PGI2 was a potent venodilator in our system. We conclude that cilazaprilat and enalaprilat are inhibitors of ACE associated with the vein wall, but there is no evidence for either drug of direct, ACE-independent, prostaglandin-mediated vasodilation.     

Oral pharmacokinetics and ascitic fluid penetration of pefloxacin in cirrhosis

Summary Plasma and ascitic fluid concentrations of pefloxacin in 10 cirrhotic patients and 8 healthy volunteers were determined following administration of a single oral dose of 400 mg.The mean elimination half-life was significantly increased in the patients (29.0 h) compared to in 8 healthy volunteers (12.3 h). In patients, the total plasma clearance (2.71 vs 6.85 l/h) and volume of distribution (1.12 vs 1.67 l/kg) were decreased. Estimated by the ratio of the AUC in peritoneal fluid and plasma, ascitic fluid penetration was 68% after one oral dose, and pronounced accumulation of pefloxacin in ascites was found after repeated doses.Oral pefloxacin would seem to be a convenient and useful treatment of spontaneous, gram-negative, bacterial peritonitis in cirrhosis. However, the decreased hepatic metabolism of the drug leads to a marked accumulation in plasma and ascites after repeated doses, and a reduced dose is required in these patients.     

Hemodynamic responses to angiotensin I in normal volunteers and the antagonism by the angiotensin-converting enzyme inhibitor cilazapril

According to classic pharmacologic theory, agonist/antagonist competition can be used to quantify an antagonist's potency by measurement of agonist dose-response curves in the presence of varying doses of the antagonist. We used this principle to characterize the interaction between angiotensin I (AI) and the angiotensin-converting enzyme (ACE) inhibitor cilazapril in humans. In addition, by comparing the effects of AI and angiotensin II before and after administration of a 30-mg dose of cilazapril, we could show the specific AI antagonism of the ACE inhibitor in humans. To obtain the antagonist's dose-response curves, six healthy male volunteers received five single oral doses of cilazapril, 0.5-8.0 mg. Enalapril, 10 mg, and captopril, 12.5 mg, served as positive controls and placebo as the negative control. Dose-response curves following intravenous infusions of AI were established 4 h after oral ingestion of the ACE inhibitors. Noninvasively measured systolic and diastolic blood pressures and total peripheral resistance assessed AI effects. Cilazapril dose dependently shifted the AI dose-response curve rightward, with 1.0 mg inducing a twofold shift. Enalapril and captopril appear less potent, on a milligram basis, in antagonizing AI effects 4 h after drug intake. The methodology could be a useful tool for a rational testing and comparison of ACE inhibitors in clinical pharmacology.     

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic alterations of quinapril during repeated treatment in elderly subjects

Objective: To examine whether the pharmacokinetics of quinaprilat, an active metabolite, change during repeated treatment with quinapril, an ACE inhibitor, in elderly subjects. Methods: Quinapril (10 mg) was given once daily for 8 days in eight elderly hypertensive subjects (76 years old). Blood samples were obtained for a 24-h period after the first and eighth doses. Results: Plasma concentrations of quinaprilat after the eighth dose were significantly higher than those after the first dose. The maximum plasma concentration (C_max) tended to be greater, and the area under the plasma concentration-time curve (AUC) was significantly greater after the eighth dose. Conclusions: The study showed an increase in quinaprilat concentrations and subsequent increase in AUC, during repeated treatment with quinapril in elderly subjects. However, the differences observed were very small and of no clinical significance. Received: 24 November 1997 / Accepted in revised form: 24 February 1998     

Pharmacokinetic characteristics of bornaprolol in healthy volunteers

1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240, 480, 960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (C1), 207 l for volume of distribution (V beta), 2.6 h for elimination half-life (t1/2 beta). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 60 l/h for C1, 1500 l for V beta, 20 h for t1/2 beta. Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-10 min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.     

Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris.

1. Epanolol is a novel anti-anginal agent which is a beta 1-adrenoceptor partial agonist exhibiting selective beta 1-adrenoceptor antagonist and selective beta 1-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/- s.d.) after the single dose (25.7 +/- 17.0 ng ml-1) were not significantly different (P = 0.35) from those at steady state (32.4 +/- 20.9 ng ml-1). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/- 29.8 ng ml-1 h) from that at steady state (78.4 +/- 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.     

Oral pharmacokinetics and ascitic fluid penetration of ofloxacin in cirrhosis

Plasma and ascitic fluid concentrations of ofloxacin were determined in 12 cirrhotic patients after a single dose and repeated 200 mg oral doses. The single dose kinetics were compared to those obtained in 12 healthy volunteers. Mean plasma elimination half-life was 11.6 h in cirrhotics and 7.0 h in controls. Mean total clearance was 2.3 times lower in patients than in controls, due to a significant decrease of renal clearance of the drug, unrelated to creatinine clearance. Mean apparent volume of distribution was 1.2 l/kg in patients and 1.8 l/kg in controls. Estimated by the ratio of AUC in peritoneal fluid and plasma, ascitic fluid penetration was 80% after the first oral dose. Ascitic fluid concentrations equaled corresponding plasma concentrations after 10 h, without pronounced accumulation of ofloxacin in ascites. We may conclude that, in cirrhotic patients with normal serum creatinine, a significant impairment of renal tubular handling of ofloxacin could be observed and led to a delayed elimination half-life of the drug. Because of its broad spectrum of activity, low side-effect profile, and large ascitic fluid penetration after oral administration, ofloxacin appears to be a new therapeutic approach of severe infections in cirrhotic patients, in particular spontaneous bacterial peritonitis.