Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Pharmacokinetics and pharmacodynamics of pentopril, a new angiotensin-converting-enzyme inhibitor in humans

In a single, ascending-dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero-order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125- and 250-mg doses, showed a dose proportional urinary recovery of 21% (+/- 5%) for pentopril and 40% (+/- 5%) for CGS 13934. In the multiple-dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half-lives (pentopril, less than 1 hr; CGS 13934, approximately 2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin-I (AI)-induced changes in blood pressure and plasma angiotensin-converting-enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10-500 mg). The pharmacodynamic half-life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI-induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half-maximal inhibition of 53 ng/mL.     

Disposition of flavodilol in laboratory animals

The disposition of flavodilol, a novel antihypertensive agent, was investigated in rats, rabbits, and dogs following iv or oral administration of 14C-flavodilol or unlabeled drug. Peak, plasma levels occurred within 6 hours of an oral dose in all three species. Following an iv dose, plasma elimination half-lives of flavodilol in rats, rabbits, and dogs were 3.0, 3.0, and 4.0 hr, respectively. Total body clearances were 0.71 liter/hr/kg for the rat, 1.89 liters/hr/kg for the rabbit, and 3.07 liters/hr/kg for the dog. Renal clearances were a small fraction of total clearance at 0.042, and 0.114 liter/hr/kg for the rat and dog, respectively, suggesting extensive nonrenal clearance. The volumes of distribution of 3.04 for the rat, 8.10 for rabbit, and 18.13 liters/kg for dog are large, suggesting significant extravascular distribution of flavodilol. Following 10 and 50 mg/kg po doses of 14C-flavodilol in rats, recovery of total radioactivity after 79 hr was 100.7% and 88.4% of the dose, respectively, most of which was recovered in the feces (77.5% and 66.6%, respectively). Tissue distribution studies of 14C in rats at 1.5, 5, 24, and 48 hr after a single po dose of 10 mg/kg 14C-flavodilol showed that the majority of the radioactivity was in the gastrointestinal tract and organs of elimination at all time points. Less than 1% of the dose remained in the body at 48 hr. 14C-Flavodilol was administered to rats iv at 1 mg/kg and orally at 10 mg/kg to assess comparative (label vs. nonlabel) absorption and distribution characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related changes in the disposition of benzyl acetate. A model compound for glycine conjugation

The in vivo metabolism and excretion of benzyl acetate (BA), a model compound for glycine conjugation, was examined in male Fischer 344 rats and C57BL/6N mice. Rats aged 3-4, 9, and 25 months received a single oral dose of either 5 or 500 mg/kg 14C-BA, while male mice aged 2, 13, and 25 months received a single oral dose of 10 mg/kg 14C-BA. Urine and feces were collected for 96 hr. Biliary excretion and plasma elimination were also examined in male Fischer rats after iv administration of 5 mg/kg 14C-BA. In both young and old rats and mice, hippuric acid (HA) was the major urinary metabolite after oral dosing of BA. No significant age-related difference was observed in rats in the urinary elimination of BA-derived radioactivity or in the percentage of the total dose excreted as hippuric acid (approximately 95%). Twenty-five-month old rats excreted a significantly higher percentage of the total dose as benzyl mercapturic acid (approximately 2%) than did 3- to 4-month-old rats (approximately 1%) at the 5 mg dose. Benzyl mercapturic acid excretion in 3- to 4-month-old rats was also increased significantly at 500 mg/kg BA vs. 5 mg/kg BA. Fecal excretion of BA-derived radioactivity declined significantly in 25-month-old rats at both the 5 and 500 mg dose. This decrease was reflected by an age-related decline in biliary excretion and higher plasma levels of BA-derived radioactivity. Examination of plasma metabolites revealed a significantly higher level of HA and benzoyl glucuronide in 25-month rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nonclinical Toxicology Studies with Zidovudine: Acute, Subacute, and Chronic Toxicity in Rodents, Dogs, and Monkeys

In single dose acute toxicity studies in CD-1 mice and CD rats,the median lethal dose (MLD) for zidovudlne (ZDV) was >750mg/kg after iv dosing and >3000 mg/kg after po administration(recommended human dose is 100 mg every 4 hr while awake). Becauseof the short half-life in rats (0.8 hr), dogs (1.0 hr), andmonkeys (0.8 hr), the daily dose of ZDV in most studies wasgiven in two equal portions approximately 6 hr apart. Intravenousadministration of ZDV was well tolerated in beagle dogs at doselevels up to 42.5 mg/kg bid for 2 weeks and in CD rats at doselevels up to 75 mg/kg bid for 4 weeks. In a 2-week dose range-findingstudy in beagle dogs, cytostatic effects were noted at po doselevels of 62.5 to 250 mg/kg bid in certain tissues with rapidcell replication rates. In contrast, in 3-to 12-month oral toxicitystudies in CD rats and cynomolgus monkeys, the principal toxicologicfinding was reversible macrocytic normochromic anemia whichoccurred at 225–250 mg/kg bid in rats and 17.5–150mg/kg bid in monkeys. In the 12-month rat study, RBC was decreasedat 25 and 75 mg/kg bid. In the 12-month monkey study WBC wasslightly decreased at 150 mg/kg bid.     

The disposition and metabolism of [14C]piritrexim in rats after intravenous and oral administration.

The disposition of [14C]piritrexim in male rats after iv (5 and 10 mg/kg) and po (5, 10, and 20 mg/kg) doses was studied. After an iv dose of 10 mg/kg, rats excreted an average of 57% of the dose in feces and 32% in urine; after a po dose of 10 mg/kg, 84% of the dose was excreted in feces and 9% in urine. After iv doses, the elimination of unchanged drug from plasma was first order, with a t1/2 of 0.6 hr; at any time point, unchanged drug accounted for less than 50% of the total radiocarbon in the plasma. Oral bioavailability of unchanged drug was less than 5%. O-Demethylation and subsequent conjugation were the main pathways of metabolism; the demethyl metabolites of piritrexim were potent inhibitors of dihydrofolate reductase and were cytotoxic to cells in culture. Concentrations of radiocarbon were highest in liver 24 hr after an iv dose, but less than 1% of the radiocarbon was unchanged drug. Concentrations of radiocarbon in liver after po doses were approximately 40% of those attained after equivalent iv doses.     

Disposition of acrivastine in the male beagle dog.

Three male beagle dogs were given 10 mg/kg iv and oral doses of [14C]acrivastine, a novel nonsedating antihistaminic agent, in a nonrandomized crossover experiment. Urine and feces were collected for 72 hr after dosing. After iv dosing, a mean of 34% was recovered in the urine, and 63% was recovered in the feces. After po dosing, a mean of 29% of the radiocarbon was recovered in the urine, and 63% was recovered in the feces (dose adjusted for 14% lost in vomitus). Acrivastine and three major metabolites were detected in the excreta. The metabolites were identified as a side-chain-reduced analog of acrivastine (metabolite 3, 270C81), a gamma-aminobutyric acid analog of 270C81 (metabolite 2), and a benzoic acid analog of 270C81 (metabolite 1). After iv dosing, 34% of the dose was excreted as parent drug, 21% as metabolite 3, 15% as metabolite 2, and 6% as metabolite 1, while after po dosing, 35% of the dose was excreted as parent drug, 18% as metabolite 3, 11% as metabolite 2, and 7% as metabolite 1. Pharmacokinetic analysis of acrivastine plasma concentration-time curves after both routes of administration indicated a mean total body clearance of 17.3 ml/min/kg, a Vss of 0.93 liter/kg, a terminal half-life of 0.7 hr, and an oral bioavailability of 40%. The apparent plasma half-life of the metabolite, 270C81, was 1.5 hr. Analysis of AUC values indicated that greater amounts of 270C81 than acrivastine circulated in plasma after both iv and po dosing, and that first-pass metabolism of acrivastine to 270C81 occurred. The results indicated that acrivastine was extensively metabolized in the dog to 270C81 and suggested that 270C81 itself underwent further metabolism to metabolites 1 and 2.     

Pharmacokinetics of LB20304, a new fluoroquinolone,in rats and dogs

The pharmacokinetics of LB20304 was investigated following intravenous (IV) and oral administration to rats and dogs. Additionally,in vitro metabolism and serum protein binding studies were also conducted. The total body clearance, apparent volume of distribution, terminal half-life, and extent of bioavailability were 21.8 ml/min/kg, 2265 ml/kg, 93.6 min, and 30.8% for rats; and 7.95 ml/min/kg, 4144 ml/kg, 363 min, and 81.1% for dogs, respectively. LB20304 was stable in the liver microsome containing NADPH generating system and its serum protein binding was 58.5–65.8% for rats, 19.1–26.6% for dogs, and 56.9–59.6% for humans. Its tissue concentration levels in liver, stomach, small intestine, and kidney were 9.5 to 26.1 times greater than plasma level, but the concentration in testis was quite low and that in brain was negligible in rats. The 48 hr urinary recovery of the dose was 44% for IV dosing and 14% for oral dosing, whereas the 48 hr biliary recovery of the dose was 6.4% for IV dosing and 4.5% for oral dosing in rats. In summary, the pharmacokinetic properties of LB20304 were characterized by its good oral absorption, long plasma half-life, and good tissue distribution.     

Effects of food on the bioavailability of CGS 16617, an angiotensin-converting enzyme inhibitor, in healthy subjects

CGS 16617, a direct-acting angiotensin-converting-enzyme inhibitor, was administered as a single dose of 20 mg in aqueous solution to 12 healthy male volunteers on two occasions in a randomized, cross-over design study. On one occasion, the dose was administered after an overnight fast; on the other occasion, it was administered after subjects ate a standard breakfast. Administration of CGS 16617 after food was associated with statistically significant decreases in peak plasma concentrations (58%) and areas under the plasma concentration-time curves (23%) compared with drug administration in the fasted state. Also, the time to peak plasma concentration was increased (57%) in a statistically significant manner when CGS 16617 was administered after food. Thus, the ingestion of food decreased both the rate and extent of absorption of this drug, but the mechanism of the interaction is unknown at present.     

Effects of two nonsulfhydryl angiotensin-converting enzyme inhibitors, CGS 14831 and CGS 16617, on myocardial damage and left-ventricular hypertrophy following coronary artery occlusion in the rat

The present study was designed to examine the effects of two new angiotensin-converting enzyme (ACE) inhibitors, CGS 14831 and CGS 16617 (3 mg/kg i. v. 1 min prior to occlusion and 4 and 24 h after occlusion), on myocardial ischemic (MI) damage and left-ventricular hypertrophy in rats. Administration of CGS 14831 or CGS 16617 inhibited angio-tensin-I-induced pressor responses by 40-100% for 4 h after each dose. Myocardial creatine phosphokinase (CK) levels were 10.6 +/- 0.6 U/mg protein in sham-MI animals, and following coronary artery occlusion for 48 h were decreased to 4.1 +/- 0.2 U/mg protein in MI + vehicle animals (p less than 0.01). CGS 14831 and CGS 16617 attenuated the decrease in CK content and resulted in 47 and 40% sparing, respectively, of the left-ventricular free wall. Neither agent attenuated the left-ventricular hypertrophy which developed following coronary artery occlusion. These data indicate that the nonsulfhydryl ACE inhibitors CGS 14831 and CGS 16617 have a significant cardioprotective effect in rats surviving 48 h, and suggest a potential therapeutic usefulness of these agents for the treatment of ischemia-induced heart failure.     

Felbamate pharmacokinetics in the rat, rabbit, and dog.

Rats, rabbits, and dogs were given single iv or single and multiple oral doses of felbamate ranging from 1.6-1000 mg/kg. Absorption of oral drug was complete in all species. The mean Cmax increased with dose from 13.9 to 185.9 micrograms/ml in rats, from 19.1 to 161.9 micrograms/ml in rabbits, and from 12.6 to 168.4 micrograms/ml in dogs. The tmax also increased with dose from 1-8 hr in rats, 8-24 hr in rabbits, and 3-7 hr in dogs. The plasma elimination half-life for the drug increased with dose from 2-16.7 hr in rats, 7.2-17.8 hr in rabbits, and 4.1-4.5 hr in dogs. A proportional increase in Cmax with dose was observed in all species up to 300-400 mg/kg doses. A biexponential equation fitted the drug plasma concentration vs. time data well. For multiple oral doses of 50 mg/kg or less, projected and observed steady-state concentrations agreed well. Animals dosed with [14C]felbamate eliminated most of the radioactivity in urine (58-87.7%), less in feces (7-23.7%), with considerable amounts in the bile. In rats, radioactivity was readily distributed into tissues and crossed the placenta and blood-brain barrier, but no accumulation in any tissue was observed. The volume of distribution was 131, 54, and 72% of body weight for rats, rabbits, and dogs, respectively. Binding of drug to rat, rabbit, and dog plasma proteins ranged from 22.4-35.9%. The overall plasma clearance of the drug for rats, rabbits, and dogs was 327, 52, and 108 ml.h-1.kg-1, respectively. Renal clearance of unchanged drug accounted for an estimated 20-35% and hepatic clearance due to metabolism for 65-80% of the overall clearance.     

Disposition and metabolism of prinomide in laboratory animals

The disposition and metabolism of prinomide, the 1:1 triethanolamine salt of 1-methyl-beta-oxo-alpha-(phenylcarbamoyl)-2-pyrrolepropionitrile (CGS 10787B), have been investigated in a number of animal species after single and multiple oral dosing with 14C-labeled and unlabeled drug. After single oral doses of 25 to 50 mg/kg of [14C]prinomide to mice, rats, hamsters, dogs, cynomolgus monkeys, and baboons, radioactivity was excreted primarily in urine, in the form of metabolites. However, in the mouse and monkey, fecal excretion was also significant. In the cynomolgus monkey, a radioactive dose of drug administered after multiple doses of unlabeled drug gave rise to peak plasma concentrations of radioactivity within 1 to 6 hr. Prinomide accounted for approximately 69% of this radioactivity. The terminal plasma half-life of the drug was 24 to 41 hr. Studies in rats with [14C]prinomide indicated that radioactivity was distributed rapidly to all tissues, with the highest levels being observed in blood and well perfused organs and tissues. The lowest levels were detected in fat, eyes, and brain. Tissue levels declined to less than 6% of peak values by 48 hr after dosing, the only exceptions being fat and kidney, which retained 14 and 17% of peak radioactivity, respectively. The metabolism of prinomide was qualitatively similar in all species investigated. Major metabolites identified were the phenyl ring p-hydroxy, M1, and the bicyclic spiro, M2, derivatives of the parent drug. Other common metabolites were M3, the phenyl ring p-hydroxy analog of M2 and a complete rearrangement product in the form of a succinimide derivative, M4.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption, plasma concentration, and excretion after single administration of 14C-(+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5- nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate hydrochloride in rats and dogs.

The absorption, plasma concentrations, and excretion of a newly synthesized calcium antagonist, TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate hydrochloride, CAS 96515-74-1) were studied following a single oral or intravenous administration of 14C-labelled compound. After oral administration, 14C-TC-81 was rapidly and well absorbed from the gastrointestinal tract. The peak plasma concentrations of radioactivity were observed at 0.5-1 h (rats) and 1-2 h (dogs) h after dosing. The elimination of the radioactivity in plasma was biphasic with a half-life of 3.8-5.2 h (a phase) and 42.9-56.2 h (beta phase) in the rats or 3.2 h (a phase) and 61.5 h (beta phase) in dogs. Maximum plasma concentrations of unchanged drug after oral administration of TC-81 to male rats at the doses of 0.5, 1.0, and 3.0 mg/kg were 1.7, 7.3 and 15.6 ng/ml, respectively. They were attained at 0.5 h after dosing in every dose examined. Plasma levels of unchanged drug declined with a half-life of 0.39-1.15 h. When TC-81 was orally administered to male dogs at the doses of 0.1, 0.2 and 0.5 mg/kg, plasma concentrations of unchanged drug reached the maximum level at 0.5 h after dosing and the values were 0.8, 3.3 and 9.6 ng/ml, respectively. They were eliminated with a half-life of 2.4-2.8 h. The absolute bioavailability of unchanged drug was estimated to be 2.6-7.0% (rats) and 5.3-15.5% (dogs) of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

The disposition of radioactivity after administration of the anthelminthic methyl-14C-5-cyclopropylcarbonyl-2-benzimidazole carbamate (ciclobendazole) to rats and dogs

1. The disposition of radioactivity has been studied in rats and dogs after administration of a new anthelminthic agent, 14C-labelled methyl-5-cyclopropylcarbonyl-2-benzimidazole carbamate (14C-ciclobendazole). 2. An oral dose of 14C-ciclobendazole (4 mg/kg) to rats was rapidly absorbed and about 70% and 20% of the dose was excreted in the faeces and urine, respectively, during 2 days. Bile duct cannulated rats excreted about 80% of the dose in 48-h bile, about 2% in the faeces and about 10% in the urine showing that an oral dose was well-absorbed and that some enterohepatic circulation probably occurred. The excretion of radioactivity in the bile was less after i.v. administration. 3. An oral dose of 14C-ciclobendazole (4 mg/kg) to dogs was mainly eliminated during 2 days with about 80% of the dose in the faeces and only about 10% in the urine. Anaesthetised bile duct-cannulated dogs, excreted between 26% and 35% of an oral dose in the bile during 24 h and up to 58% of an oral dose was absorbed at this time. 4. The tissue distribution of radioactivity in rats and dogs after single or multiple oral doses of 14C-ciclobendazole (4 mg/kg) showed that there was no unusual accumulation or localisation of radioactivity in the measured tissues. Highest concentrations were present in the intestinal tract, liver and kidneys, organs associated with biotransformation and excretion and also in the lungs and adrenals. 5. After oral administration of 14C-ciclobendazole to rate at three different dose levels (4, 40 and 400 mg/kg), peak plasma levels occurred at 15-30 min and declined with similar half-lives (about 20 h). A comparison of peak concentrations and areas under the plasma concentration-time relationships showed that the absorption of ciclobendazole was probably dose-dependent, a lower proportion probably being absorbed at higher doses. After repeated daily oral dosing with 14C-ciclobendazole (4 mg/kg), there were no significant changes in either the daily plasma concentrations or the biological half-life measured after the last dose, indicating that ciclobendazole probably did not induce or inhibit its own metabolism when dosed repeatedly at 4 mg/kg. 6. A comparison of the areas under the plasma concentration-time relationships after oral, i.p. and i.v. administration of 14C-ciclobendazole to rates indicated that there was no signigicant uptake by the liver during first pass and that an oral dose was well absorbed by rats. 7. The peak plasma concentration in the dog, after an oral dose of 14C-ciclobendazole (4 mg/kg) was reached at about 30 min and declined with a half-life of about 3 h. 8. Ciclobendazole was probably well-absorbed by rats and dogs and excreted more rapidly by the latter species than by the former Relatively higher plasma concentrations of drug and/or metabolites were thus achieved in rats than in dogs.     

The disposition and metabolism of a hypnotic benzodiazepine, quazepam, in the hamster and mouse

The disposition of 14C-quazepam (7-chloro-(2,2,2-trifluoroethyl) [5-14C]-5-o-fluorophenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-thione), a new benzodiazepine hypnotic, was studied in hamsters and mice after iv and po dosing. In both species, quazepam was rapidly absorbed, as indicated by the plasma Cmax being reached within 1 hr of an oral dose (5 mg/kg). Also, radioactivity is essentially completely absorbed in both species, since the percentage of dose excreted in the urine was not dependent on the route of drug administration. Radioactivity was widely distributed in the tissues of both species; however, it was concentrated (relative to plasma) only in the liver and kidneys. In hamsters, 66-77% of the radioactivity was excreted within 48 hr, and 97% within 7 days of dosing (57% found in urine and 40% in feces after iv; 54% in urine and 43% in feces after po dosing). In mice, 86-88% of the radioactivity was excreted within 24 hr, and 98% within 4 days of dosing (43% in urine and 56% in feces after iv, 37% in urine and 61% in feces after po dosing). In both species, plasma levels of quazepam, measured by GLC, accounted for a very small percentage of plasma radioactivity and the elimination half-life was short (2.4 hr in hamster and 1.2 hr in mice), indicating extensive first pass metabolism for this drug. TLC analysis of plasma and urine extracts from both species showed biotransformation of quazepam involved substitution of oxygen for sulfur, followed by: (a) N-dealkylation, 3-hydroxylation, and conjugation or (b) 3-hydroxylation and conjugation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolism of [14C]rimantadine hydrochloride in rats and dogs.

Metabolism and route of excretion of [14C]rimantadine hydrochloride was studied in male rats after single po (60 mg/kg) and iv doses (15 mg/kg) and in male dogs (5 or 10 mg/kg po and 5 mg/kg iv). Total 14C excretion in urine (po and iv) in both species reached 81-87% of the dose in 96 hr. Rimantadine was excreted in rats free (1.0% po, 1.7% iv) and conjugated (0.8% of the dose, po and iv, both in 24 hr) and in dogs, free (2.6% po, 3.0% iv) and conjugated (6.4% po, 7.7% iv, both in 48 hr). In both species, rimantadine metabolism is essentially independent of the route of administration. In rats and dogs, m-hydroxyrimantadine (mostly unconjugated) was the major metabolite, 22% (po) and 24% (iv), and 27% (po) and 21% (iv), respectively. Rats, but not dogs, excreted trans-p-hydroxyrimantadine (23.5% and 25.2%, po and iv, free plus conjugated). An oxidative pathway in dogs produced the m- and p-hydroxylated analogs with a hydroxyl in place of the amino group (3.7% and 5.7% of the dose, both conjugated). A p-hydroxylated compound with a nitro group in place of the amino group may have originated from an N-hydroxy metabolite by spontaneous oxidation during isolation. Comparison of total 14C excretion, in rats (81%, po; 82%, iv) and dogs (81%, po; 84%, iv) after po and iv administration after 96 hr indicates good absorption of rimantadine.     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.     

CGS 35601 and its orally active prodrug CGS 37808 as triple inhibitors of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting enzyme

CGS 35601 is a potent triple inhibitor of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting enzyme. It inhibited the activities of these three enzymes with IC50 values of 55, 2 and 22 nM, respectively. In conscious rats, CGS 35601 suppressed the big endothelin-1-induced pressor response by 82% and 72% at 30 and 120 minutes, respectively, following injection at a dose of 10 mg/kg, intravenously. At the same dose, CGS 35601 increased plasma atrial natriuretic peptide (ANP) immunoreactivity by 170% for up to 4 hours in conscious rats infused with ANP, and it inhibited the angiotensin I-induced pressor response by 74-94% within the first 2 hours after dosing. Similar in vivo activities were also observed with its orally active prodrug, CGS 37808. This compound blocked the big endothelin-1- induced pressor response by 71% and 67% at 30 and 120 minutes, respectively, after an oral dose of 10 mgEq/kg in conscious rats. It also increased plasma ANP immunoreactivity by 103% for up to 4 hours and inhibited the angiotensin I-induced pressor response by an average of 49% within the first 4 hours after the same dosing regimen. By suppressing the biosyntheses of endothelin-1 and angiotensin II, two potent vasoconstrictors, while simultaneously potentiating the circulating levels of ANP, a vasorelaxant and diuretic, CGS 35601 and CGS 37808 may represent novel agents for the treatment of cardiovascular and renal diseases.     

Disposition of radiolabeled BMS-204352 in rats and dogs

BMS-204352, a maxi-K channel opener, is currently under development for the treatment of stroke. The objective of this study was to determine the pharmacokinetics, mass balance and absolute oral bioavailability of [(14)C]-BMS-204352 in rats and dogs. [(14)C]-BMS-204352 was administered, to rats (n=10/group; parallel design, 6 mg/kg) and dogs (n=4/group; crossover design, 2 mg/kg), as an oral (PO) or as a 3-min intraarterial (IA) infusion in rats and a 6-min intravenous (i.v.) infusion in dogs. Blood, urine, and feces samples were collected and analyzed for unchanged BMS-204352 (plasma) using a validated LC/MS assay and for total radioactivity (plasma, urine, feces) using liquid scintillation counting. The mean total body clearance (CLT) and steady-state volume of distribution (VSS) values for the unchanged BMS-204352 were 2.58 +/- 0.48 l/h/kg and 6.3 +/- 1.14 l/kg, respectively, in rats and 0.21 +/- 0.02 l/h/kg and 4.06 +/- 0.47 l/kg, respectively, in dogs. In both species, the elimination half-life of total radioactivity was significantly longer as compared to the unchanged drug. After IA administration of radiolabeled BMS-204352 to rats, ca. 5.9 and 85% of radioactivity was recovered within 7 days in urine and feces, respectively; corresponding recoveries after PO dosing were 4.5 and 99.5%, respectively. The recoveries were similar in dogs, i.e., ca. 5.2 and 83% of administered radioactivity recovered in urine and feces, respectively, for IV dose and ca. 4 and 86%, respectively, for PO dose. These data indicate that nonrenal (biliary) elimination in both species was predominant. Based on comparable urinary recovery of radioactivity and plasma AUCs of radioactivity, the extent of oral absorption of BMS-204352 appeared to be complete in both species. The absolute oral bioavailability was 55% in rats and 79% in dogs. Bioavailability and extent of absorption data suggest evidence of first pass metabolism of BMS-204352 in the rat and dog.