Pharmacokinetics of the angiotensin-convertingenzym e inhibitor,benazepril, and its active metabolite,benazeprilat, in dog

1. The pharmacokinetics of the angiotensin-converting-enzyme (ACE) inhibitor benazepril were evaluated in eight healthy Beagle dogs. Benazepril was administered orally at a dosage of 7·5?mg (about 0·5?mg/kg) both as a single dose and then once daily for 14 consecutive days. The prodrug, benazepril, and its active metabolite, benazeprilat, were measured in plasma using a gas chromatography mass-spectrometry method with massselective detection. 2. Benazepril appeared quickly in the plasma (t_max 0·5?h) and was rapidly eliminated by max metabolism to benazeprilat. Peak benazeprilat concentrations were attained later (t_max 1·25?h) and declined biphasically with a rapid elimination phase (t_½λ₁ 1·1 and 1·7?h after single and the last repeated dose respectively) followed by a terminal elimination phase (t_½λ_Z 11·7 and 19·0?h after single and repeated dose respectively). The mean residence time for benazeprilat was 15·2?h after the single dose and 17·4?h after the 14th dose. 3. Repeated administration of benazepril produced moderate bioaccumulation of benazeprilat; the ratio of AUC_{[0→24 h]}'s after the 14th dose as compared with the single dose was 1·47, equivalent to a half-life for accumulation (t_½acc) of 14·6?h. Steady-state benazeprilat concentrations at peak (C_max) and trough (C_min) were reached within three doses. 4. The pharmacodynamics of benazepril were assessed by measurement of plasma ACE activity. After both single doses and at steady-state, benazepril produced inhibition of ACE activity in all dogs that was maximal at peak effect (E_max = 100%) and long-lasting max (> 85% inhibition was present at 24?h). The long duration of action of benazepril on plasma ACE is due to the presence of the terminal elimination phase of benazeprilat, even though most of the metabolite is rapidly eliminated from the plasma.     

Disposition of [14C]-benazepril hydrochloride in rat, dog and baboon. Absorption, distribution, kinetics, biotransformation and excretion

The compound 3-[(1-ethoxycarbonyl-3-phenyl-(1S)-propyl)-amino]-2,3,4,5- tetrahydro-2-oxo-1-(3S)-benzazepine-1-acetic acid hydrochloride (benazepril.HCl, CGS 14 824 A) is an ethyl ester prodrug of the angiotensin converting enzyme (ACE) inhibitor benazeprilat (CGS 14 831). The disposition of both compounds was studied in rat, dog and baboon after peroral and intravenous dosing of 14C-labelled preparations (2.5-3 mg/kg). Perorally dosed benazeprilat was poorly absorbed in rats, whereas benazepril.HCl was well absorbed in all species. Onset of absorption of benazepril.HCl was fast. Plasma concentrations of radioactivity indicated a prolonged absorption process. Upon intravenous benazepril.HCl, plasma levels declined rapidly in all species but showed a slow terminal elimination phase. Distribution to all organs and tissues occurred rapidly and was typical for an acid compound. Passage of the blood-brain barrier and of the placenta occurred to a minimal extent. No accumulation was observed after repeated dose. Radioactivity was rapidly and completely eliminated; biliary excretion was important. In the rat, benazepril was completely hydrolysed by first pass metabolism to the pharmacologically active benazeprilat. In dog and baboon hydrolysis was incomplete and additional hydrophilic metabolites were formed also.     

The influence of hepatic cirrhosis on the pharmacokinetics of benazepril hydrochloride

The influence of hepatic disease on the pharmacokinetics of the new ACE inhibitor, benazepril hydrochloride, was evaluated in 12 male patients suffering from liver cirrhosis. The patients received a single oral 20 mg dose. The plasma concentrations and urinary excretion of unchanged benazepril and its active metabolite benazeprilat were determined. Compared with a historical control group of healthy volunteers treated with the same benazepril. HC1 dose, the plasma concentrations of benazepril were doubled in the cirrhotic patients. However, the time to reach maximum concentration (0.5 h) was not affected. The plasma kinetics and the urinary excretion of the metabolite benazeprilat were not significantly altered: Area under the curve and maximum concentration as well as time to maximum concentration (1.5 h) were comparable with those in the healthy subjects. There was also no significant difference between the two populations for the total urinary excretion and the renal clearance of benazeprilat. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 94 per cent, respectively). In conclusion, the rate and the amount of bioactivation of the inactive prodrug benazepril to the active benazeprilat were virtually unaffected by hepatic cirrhosis. Thus, there seems to be no need for dosage adjustment of benazepril hydrochloride in patients suffering from cirrhosis of the liver.     

Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril.HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril.HCl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10 mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once-daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril.HCl was rapidly absorbed (tmax = 0.5 h) and rapidly eliminated from plasma (t1/2 = 0.6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax = 1.5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t 1/2 = 2.7 h), whereas the terminal phase (t1/2 = 22.3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24-h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1.20 for AUC and 1.24 for urinary excretion. The effective half-life for accumulation was estimated at about 10-11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.     

Pharmacokinetics and pharmacodynamics of the ace inhibitor benazepril hydrochloride in the elderly

Summary The pharmacokinetics and pharmacodynamics of a single oral dose benazepril·HCl 10 mg have been studied in 15 healthy volunteers aged 65 to 80 y. The kinetics of unchanged benazepril and its active metabolite benazeprilat did not differ significantly in males and females, so the combined kinetic data from all 15 elderly subjects were compared with a historical control group of 19–32 year-old healthy men treated in the same way.The disposition of benazepril was not affected by age. The time to maximum plasma concentration, t_max (0.5 h) and elimination half-life (0.6 h) in the elderly were the same as in young subjects. The kinetics of benazeprilat was slightly changed in the elderly; although its t_max (1.5 h) was not affected, C_max and the AUC were 20–40% greater. The elimination half-life of benazeprilat during the first 24 h after doing in the elderly was increased by about 20% to 3.2 h. The renal plasma clearance of benazeprilat (18.1 ml·min^–1) was about 20% smaller than in the young subjects. An average of 18.5% of the dose was recovered as benazeprilat in the 24 h urine from the elderly subjects, which was similar to the recovery in the young subjects. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 95%, respectively).Mean systolic and diastolic blood pressures in the elderly were reduced by a maximum of 37/16 mm Hg at 6 h, in association with a small rise in pulse rate.Treatment was generally well tolerated. Three of the 15 subjects reported clinical adverse experiences judged to be possibly drug related, namely headache, abdominal pain and cold extremities.Summary results were reported in the Proceedings of a Sattelite Symposium of the X^th Congress of the European Society of Cardiology, 1988, Vienna, Austria [1].     

The disposition of [14C]-labelled benazepril HCl in normal adult volunteers after single and repeated oral dose

1. The disposition of [14C]-labelled benazepril HCl, an ACE-inhibitor, was studied in four normal adult volunteers after a single oral dose of 20 mg and after repeated doses of 20 mg once daily for 5 days. Radioactivity was measured in plasma, urine and faeces. The prodrug ester benazepril and the pharmacologically active metabolite benazeprilat were determined quantitatively in plasma and urine by a g.c.-m.s. method. The pattern of metabolites in urine was analysed semiquantitatively by h.p.l.c.-radiometry. 2. After a single oral dose at least 37% was absorbed, as indicated by urinary recovery. The peak plasma concentration of benazepril (0.58 +/- 0.13 nmol/g (SD] was observed at 0.5h after dose, indicating rapid absorption. Peak concentrations of radioactivity (1.88 +/- 0.48 nmol/g) and of active benazeprilat (0.84 +/- 0.25 nmol/g) were observed at 1 h after dose, demonstrating rapid bioactivation. 3. The area under the plasma curve (AUC0-96 h) of total radioactivity amounted to 9.7 +/- 1.1 (nmol/g)h, 5% of which was accounted for by benazepril and about 50% by benazeprilat. 4. Over 9 days 96.8 +/- 0.5% of the dose was excreted in urine and faeces. Urinary excretion accounted for 37.0 +/- 6.0% of the dose, 80% of which was recovered in the first 8 h after dosing. 5. In urine, only 0.4% of the dose (1% of the radioactivity) was excreted as unchanged benazepril, indicating that the compound was extensively metabolized. Benazeprilat accounted for 17% of the dose (about half of the radioactivity; 0-96 h). Glucuronide conjugates of benazepril and benazeprilat constituting approximately 11% and 22% of the radioactivity (about 4% and 8% of the dose; 0-48 h) were tentatively identified. 6. Repeated oral treatment with benazepril HCl did not influence the pharmacologically relevant kinetics and disposition parameters.     

Pharmacokinetics and pharmacodynamics of benazepril in hypertensive patients with normal and impaired renal function.

The pharmacokinetics and pharmacodynamics of benazepril, an angiotensin converting enzyme (ACE) inhibitor, were investigated after administration of a single oral 5-mg dose and 7 more doses on consecutive days to hypertensive patients with normal renal function (NRF) and those with impaired renal function (IRF). The antihypertensive effect of benazepril was observed as early as 30 min after a single dose, and those effects during consecutive dosing were also sustained for 24 h with a lesser diurnal variation in blood pressure (BP). The time to peak (Tmax) and the apparent elimination half-life (t1/2) for benazepril were 0.6-0.7 h and 0.4-0.8 h, respectively. Tmax for its diacid was 1.5-2.4 h in both groups. The area under the plasma concentration-time curve to 24 h (AUC0-24h) for the diacid was significantly greater in the IRF group than in the NRF group. After consecutive dosing of benazepril, AUC0-24h and plasma peak level (Cmax) were significantly increased in the IRF group. Serum ACE activity was markedly suppressed for 24 h after administration, and the inhibition was closely related to plasma diacid levels. A significant inverse correlation was observed between creatinine clearance and the AUC for the diacid. These results suggest that benazepril is rapidly bioactivated to diacid and exhibits rapid onset and long-lasting antihypertensive effects. Dosage reduction might be required to minimize unnecessary drug accumulation in patients with severe IRF.     

The disposition of [14C]-labelled benazepril HC1 in normal adult volunteers after single and repeated oral dose

1. The disposition of [¹⁴C]-labelled benazepril HC1, an ACE-inhibitor, was studied in four normal adult volunteers after a single oral dose of 20 mg and after repeated doses of 20 mg once daily for 5 days. Radioactivity was measured in plasma, urine and faeces. The prodrug ester benazepril and the pharmacologically active metabolite benazeprilat were determined quantitatively in plasma and urine by a g.c.-m.s. method. The pattern of metabolites in urine was analysed semiquantitatively by h.p.l.c.-radiometry.

2. After a single oral dose at least 37% was absorbed, as indicated by urinary recovery. The peak plasma concentration of benazepril (0.58. 0.13 nmol/g (SD)) was observed at 0.5 h after dose, indicating rapid absorption. Peak concentrations of radioactivity (1.88.0.48 nmol/g) and of active benazeprilat (0.84. 0.25 nmol/g) were observed at 1 h after dose, demonstrating rapid bioactivation.

3. The area under the plasma curve (AUC_0-96h) of total radioactivity amounted to 9.7. 1.1 (nmol/g) h, 5% of which was accounted for by benazepril and about 50% by benazeprilat.

4. Over 9 days 96.8. 0.5% of the dose was excreted in urine and faeces. Urinary excretion accounted for 37.0. 6.0% of the dose, 80% of which was recovered in the first 8 h after dosing.

5. In urine, only 0.4% of the dose (1% of the radioactivity) was excreted as unchanged benazepril, indicating that the compound was extensively metabolized. Benazeprilat accounted for 17% of the dose (about half of the radioactivity; 0-96 h). Glucuronide conjugates of benazepril and benazeprilat constituting approximately 11% and 22% of the radioactivity (about 4% and 8% of the dose; 0-48 h) were tentatively identified.

6. Repeated oral treatment with benazepril HC1 did not influence the pharmacologically relevant kinetics and disposition parameters.     

Clinical pharmacokinetics of the newer ACE inhibitors. A review

The orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group. Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is converted in vivo to captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information. A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%. It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short. Impaired renal function decreases the elimination rate of the diacids.(ABSTRACT TRUNCATED AT 400 WORDS)     

The absence of a pharmacokinetic interaction between aspirin and the angiotensin-converting enzyme inhibitor benazepril in healthy volunteers

Potential effects of the coadministration of single doses of aspirin (325 mg) and of benazepril hydrochloride (20 mg) on the pharmacokinetics and the metabolism of these two drugs were evaluated in 12 healthy subjects. Plasma concentration profiles of benazepril, its active metabolite benazeprilat, and total salicylic acid were determined together with urinary excretion of benazeprilat, salicylic acid, salicyluric acid, and salicylate glucuronides. Almost superimposable plasma profiles of benazepril, benazeprilat, and total salicylic acid were achieved with the drugs given alone and concomitantly. The coadministration of benazepril hydrochloride and aspirin did not modify the pharmacokinetics or the metabolism of the two drugs.     

Antihypertensive mechanism of action of the novel angiotensin converting enzyme inhibitor benazepril. Effect on isolated vascular preparations

Benazepril (CGS 14824A HCl) is a new prodrug type angiotensin converting enzyme (ACE) inhibitor. The active form is considered to be benazeprilat, a diacid hydrolyzed compound. Benazepril and benazeprilat inhibited the contraction induced by exposure with angiotensin I, not angiotensin II, in the isolated rabbit aorta. The ACE inhibiting activity of benazeprilat was 1000 times more potent than that of benazepril in this experiment. Benazepril as well as benazeprilat and captopril exerted little influence on norepinephrine, serotonin and high K(+)-induced contraction or bradykinin-induced relaxation in isolated blood vessel preparations, thus angiotensin II synthesis inhibition seemed to be the main cause for its vasodilation. Benazepril, unlike benazeprilat or captopril showed considerable influence on prostaglandin (PG)-induced responses at higher concentrations. The vasocontraction induced by PGF2 alpha was competitively antagonized at 10(-5)-10(-4) mol/l, while vascular responses induced by PGE1, PGE2 or PGI2 was inhibited at 3 x 10(-4) mol/l of benazepril. Although these influences on PGs might not contribute much to its vasodilatory mechanism, the action seemed interesting in relation to cough induction, a known side effect of ACE inhibitors in the market. Benazepril has two asymmetric carbon atoms, thus four optical isomers are possible, SS (benazepril), SR (CGP 14'829A), RS (CGP 42'454A), RR (CGP 42'456A). The SS configuration was the most potent for antagonizing angiotensin I-induced vasocontraction, which seemed to be the best fitted for the ACE molecule.     

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)     

Pharmacokinetics of pirprofen in young volunteers and elderly patients

Summary Plasma concentrations of pirprofen were measured in 11 elderly arthritic patients and 6 healthy young volunteers at the beginning and end of 8 days treatment with 400 mg doses twice daily. The mean ages of the two groups were 74.5 and 21.8 years, respectively. There were no statistically significant differences in peak concentrations, times to peak, areas under the curve or terminal elimination half-lives between the groups after single dosing. Repeated dosing increased plasma drug concentrations in both groups but the extent was as predicted from the single dose data. Again there were no statistically significant differences between the groups, although pre-dosing plasma concentrations were higher in the elderly compared with the young individuals. The results of this relatively small study suggest that advancing age and arthritic disease appear to have little influence on the pharmacokinetics of pirprofen and no modification in the dosage recommendation in elderly patients without overt renal or hepatic impairment is indicated.     

Comparative single dose and steady-state pharmacokinetics of bevantolol in young and elderly subjects

Summary The pharmacokinetics of bevantolol were examined following single and repeated oral doses to young and elderly volunteers. Following administration of a single 200-mg bevantolol tablet mean maximum plasma bevantolol concentrations in young and elderly subjects were 1690 ng/ml and 1810 ng/ml, respectively. Maximum bevantolol concentrations occurred approximately 1.1 h postdose in both young and elderly subjects. There were no significant differences in mean steady state bevantolol concentrations on Day 14 between young and elderly subjects. However, disproportionate increases in C_max, and in AUC, but not in t_max values were observed between Days 1 and 14.On Days 1 and 14, most young and elderly subjects exhibited monoexponential decline in bevantolol plasma concentrations after absorption phase. In those subjects Day 14 elimination half-lives in young and elderly were 1.9 and 2.2 h, respectively. In subjects who exhibited biexponential decline in bevantolol, an age effect in elimination became apparent, on Day 14 elimination half-lives were 5.7 and 11.2 h in young and elderly subjects, respectively. Bevantolol Metabolite III concentrations were observed in plasma of some subjects during the first 6 h after dosing. At steady-state AUC (0-ldc) values for the metabolite were less than 2% those of bevantolol.Bevantolol plasma levels accumulate to a small extent with repeated 200 mg daily doses. This is probably due to the contribution of a late and more persistent terminal elimination phase that was discernable in only certain individuals.     

Observation on the efficacy and pharmacokinetics of betaxolol (SL 75212), a cardioselective beta-adrenoceptor blocking drug.

1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10, 20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times. The maximum effect (34.4 +/- 2.2%) occurred after 40 mg. 3 There was a small decline in effect from the peak to 24 h when 40 mg produced a 23.3 +/- 2.7% reduction and a further decline to 48 h when there was a 14.6 +/- 1.8% reduction. 4 Plasma levels of betaxolol were measured in these studies. The peak plasma concentration occurred between 3 and 8 h with different doses. The plasma elimination half-lives after 10, 20 and 40 mg were 11.4 +/- 2.5, 15.9 +/- 4.9 and 15.1 +/- 3.1 h. 5 The effects of 40 mg betaxolol, 200 mg atenolol, 160 mg propranolol, 160 mg oxprenolol, 400 mg sotalol and placebo on an exercise tachycardia were compared in five subjects who received all treatments in random order. 6 There was no significant difference in the maximum reduction produced in an exercise tachycardia by the different drugs. 7 The effect of all drugs decreased with time. The effect of oxprenolol had worn off at 24 h but at 48 h only atenolol and betaxolol produced significant reductions in the exercise tachycardia. 8 Plasma concentrations of the different drugs were measured and plasma elimination half-lives determined. The half-life for betaxolol was 24.5 h which was longer than that for any of the other drugs. 9 These observations show that betaxolol is a potent beta-adrenoceptor antagonist with a long duration of effect on an exercise tachycardia and a long plasma elimination half-life.     

Pharmacokinetic studies with benoxaprofen in man: prediction of steady-state levels from single-dose data.

1 Plasma levels of benoxaprofen were measured in eight subjects 2-168 h after a single oral dose of 100 mg. Pharmacokinetic parameters were estimated by the NON-LIN computer programme using the two-compartment open model. Mean half-lives of absorption, distribution and elimination were respectively 0.4, 4.8 and 37.6 hours. Volumes of distribution were 6.8 and 3.2 litres for the central and peripheral compartments respectively. 2 Eleven subjects in groups of three or four were given 25 mg/day, 50 mg/day or 100 mg two times daily for 11 days. Their plasma levels were compared with those predicted from the above parameters, which were adjusted for individual body weights and elimination half-lives. Steady-state plasma levels were predicted in each case, and a resonable degree of accuracy (mean 91%) achieved. 3 There was no tendency for observed and predicted levels to diverge as the dose was increased, and there was no evidence of any change in the disposition of benoxaprofen on repeated dosing. 4 The pharmacokinetic parameters were used to predict steady state plasma levels for various dosage regimens.     

Elimination of cocaine and metabolites in plasma, saliva, and urine following repeated oral administration to human volunteers

Chronic administration of lipophilic drugs can result in accumulation and prolonged elimination during abstinence. It has been suggested that cocaine and/or metabolites can be detected in saliva and urine for an extended period following long-term, high-dose administration. The effects of chronic oral cocaine administration in healthy volunteer subjects with a history of cocaine abuse were investigated. Subjects were housed on a closed clinical ward and were administered oral cocaine in up to 16 daily sessions. In each session, volunteers received five equal doses of oral cocaine with 1 h between doses. Across sessions, cocaine was administered in ascending doses from an initial dose of 100 mg (500 mg/day) up to 400 mg (2 g/day), increasing by 25 mg/dose/session (125 mg/session). Participation in the study was terminated if cardiovascular safety parameters were exceeded. Plasma and saliva specimens were collected periodically during the dosing sessions and during the one-week withdrawal phase at the end of the study. All urine specimens were collected throughout the entire study. Specimens were analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatographic-mass spectrometric analysis in the SIM mode. The limit of detection for each analyte was approximately 1 ng/mL. The analytes measured included benzoylecgonine (BZE), ecgonine methyl ester, cocaine, benzoylnorecgonine, norcocaine, m- and p-hydroxycocaine, and m- and p-hydroxybenzoylecgonine. Noncompartmental analysis was employed for the determination of plasma and saliva pharmacokinetic parameters. Urinary elimination half-lives for cocaine and metabolites were determined by constructing ARE (amount remaining to be excreted) plots. Two phases of urinary elimination of cocaine and metabolites were observed. An initial elimination phase was observed during withdrawal that was similar to the elimination pattern observed after acute dosing. The mean (N = 6) plasma, saliva, and urine cocaine elimination half-lives were 1.5 +/- 0.1 h, 1.2 +/- 0.2 h, and 4.1 +/- 0.9 h, respectively. For three subjects, the mean cocaine urinary elimination half-life for the terminal phase was 19.0 +/- 4.2 h. There was some difficulty in determining if a terminal elimination phase for cocaine was present for the remaining three subjects because of interference by high concentrations of BZE. A terminal elimination phase was also observed for cocaine metabolites with half-life estimates ranging from 14.6 to 52.4 h. These terminal elimination half-lives greatly exceeded previous estimates from studies of acute cocaine administration. These data suggest that cocaine accumulates in the body with chronic use resulting in a prolonged terminal elimination phase for cocaine and metabolites.     

Pharmacokinetics of ciprofloxacin. 1st communication: absorption, concentrations in plasma, metabolism and excretion after a single administration of [14C]ciprofloxacin in albino rats and rhesus monkeys

The absorption, disposition, metabolism and excretion of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3- quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) were studied following a single intraduodenal (rat), oral and intravenous (rat, monkey) administration, respectively, in the dose range 5 to 30 mg/kg body weight. Ciprofloxacin was absorbed partially (30 to 40%) in both species. Peak plasma concentrations of radioactivity were measured approximately 1 h (rat) or 2 h (monkey) after oral dosing. Terminal half-lives ranging from 26 to 44 h were determined for the elimination of radioactivity from the plasma (observation time up to 48 h after dosing). Nearly identical concentrations of the unchanged drug and total radioactivity were found during the first 7 or 8 h for the monkey after intravenous injection and for the rat also after oral administration, respectively. After reaching maximum concentration of 0.25 microgram/ml after administration of 5 mg/kg to rats and 0.88 microgram/ml after dosing with 30 mg/kg to a rhesus monkey, the unchanged drug was eliminated from plasma corresponding to half-lives ranging from 3 h (rat) and 4.4 h (monkey). The radioactivity was rapidly and completely excreted in both species. After intravenous administration about 51% (rat) and 61% (monkey), respectively, was excreted via the kidney. After oral dosing renal excretion amounted to 6-14% (rat) and 30% (monkey), respectively. Maximum residues in the body (exclusive gastrointestinal tract) of 1% of dose occurred in both species. In urine and feces of rats predominantly the unchanged drug and a conjugate were detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and excretion of phenol red in the channel catfish.

1. Disposition of phenol red was examined in channel catfish (Ictalurus punctatus) after oral or intravascular (i.v.) dosing at 10 mg/kg body weight. 2. Phenol red was not detectable in plasma, urine, or bile after oral administration. 3. After i.v. dosing, plasma concentrations of phenol red were best described by a two-compartment pharmacokinetic model with distribution and elimination half-lives of 2.3 and 21 min, respectively. The apparent volume of distribution at steady state (Vss) was 225 ml/kg and total body clearance (Clb) was 658 ml/h per kg. Plasma protein binding was 19%. 4. Biliary excretion was the primary route of elimination of phenol red; in 24 h, 55% of the i.v. dose was excreted in bile compared with 24% in urine. No metabolites were detected in these fluids. 5. The use of anaesthesia during dosing had no effect on the quantitative excretion of phenol red by renal or biliary routes.     

Plasma levels of ethaverine after oral administration to humans

Fourteen healthy human subjects received a 200 mg oral dose of ethaverine hydrochloride as an elixir. Blood samples were obtained for 12 h after dosing. Plasma ethaverine concentrations were determined using a paired-ion, reversed-phase high performance liquid chromatographic method. Individual plasma concentration-time profiles were fitted to a two-compartment model with first-order absorption. The ethaverine was rapidly absorbed, based on a time of maximum plasma concentration of 0.75 h, a time-lag of 8.4 min, and an apparent first-order absorption half-life of 8.6 min. The mean terminal elimination half-life was 3.3 h.