Intestinal absorption of captopril and two thioester analogs in rats and dogs.

The objectives of this study were (i) to determine whether the reduced absorption of captopril from the colon of humans also occurs in rats and (ii), after confirmation of the relevance of a new rat model, to evaluate the intestinal absorption of captopril and several of its analogs. A model was developed and validated in which specific sites within the GI tract of rats were surgically implanted with a cannula such that animals could be dosed while conscious and unrestrained. The absorption of captopril after administration into the lower GI tract of rats was significantly reduced relative to the upper GI tract, which was consistent with results reported previously in humans.

Relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of orally administered 14C-fosinopril sodium in dogs. In vivo and in vitro studies.

The relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of the orally administered prodrug, fosinopril sodium (FS), to the active angiotensin-converting enzyme (ACE) inhibitor, SQ 27,519 (S), was determined. Two dogs each received 14C-FS by the following routes of administration: oral, intraportal, and intra-arterial. Extraction ratios (E) for the gut and liver were calculated based on the relative ratios of the AUC of FS in arterial plasma after administration of FS by various routes.

Biotransformation of tipredane, a novel topical steroid, in mouse, rat, and human liver homogenates.

The in vitro biotransformation pathways of 3H-tipredane (3H-TP) were studied. 3H-TP, at concentrations of 1 and 250 microM, was incubated with the 10,000g supernatant fraction of the liver homogenates of mice, rats, and one human. The incubation mixtures were deproteinated with methanol and, after removal of methanol by evaporation, extracted with dichloromethane.

Rapid metabolic inactivation of tipredane, a structurally novel topical steroid.

[3H]Tipredane ([3H]TP), [3H]triamcinolone acetonide ([ 3H]TAAC), [3H]hydrocortisone ([3H]HC), and [3H]betamethasone-17 alpha-valerate ([3H]BMV), each at a concentration of 1 microM, were separately incubated with the 10,000 g supernatant fraction of the liver and skin homogenates of humans, rats and mice (BMV was studied only in human liver). Sequential samples were taken for up to 1 h during each incubation. The radioactivity in each sample was extracted with methanol, and the methanolic extracts were analyzed by high performance liquid chromatography.

Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases.

Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins.

Relationship between metabolism and pharmacologic activity of SQ 27,786, an angiotensin converting enzyme inhibitor with potent diuretic activity.

SQ 27,786 is a sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor, which also possesses potent diuretic activity in dogs after intravenous administration. The absorption, distribution, metabolism and elimination of 35S-labeled SQ 27,786 was studied in dogs to determine if the observed pharmacologic activities were intrinsic to this compound or the result of metabolism to separate ACE-inhibitory and diuretic moieties. The poor pharmacologic activity observed after oral administration was found to be due to poor absorption of the ACE-inhibitory-diuretic compound.

Application of pharmacokinetics in drug safety evaluation.

The discipline of pharmacokinetics plays an important role in safety evaluation of drugs. In this presentation various kinds of pharmacokinetic studies have been discussed with specific examples of the studies that should be conducted in support of safety evaluation of new drugs. The design and evaluation of toxicologic and pathologic studies in animals, as well as of safety and efficacy studies in man, should take into consideration the pharmacokinetic characteristics of drugs.

Tissue distribution of 14C- and 35S-captopril in rats after intravenous and oral administration.

35S-Captopril (50 mg/kg) administered i.v. to rats resulted in radioactivity being widely distributed into highly vascular tissues and into excretory organs.

Distribution of aztreonam into fetuses and milk of rats.

Subcutaneous administration of [14C]aztreonam (150 mg/kg) to pregnant rats was followed by the appearance of radioactive moieties in fetuses and amniotic fluid. Concentrations of both total radioactivity and unchanged aztreonam in maternal serum declined more rapidly than those in fetuses and amniotic fluid. [14C]aztreonam (150 mg/kg) was also administered subcutaneously to lactating rats.

Distribution of [14C]aztreonam in rat tissue.

[14C]aztreonam was administered intramuscularly (50 mg/kg) to male and female rats. Groups of 10 rats (five male and five female) were sacrificed at 0.25, 2, 6, and 24 h after dosing.

Quantitative determination of captopril in blood and captopril and its disulfide metabolites in plasma by gas chromatography.

A sensitive, quantitative gas chromatographic-electron capture (GC-EC) method for the determination of captopril in blood and captopril and its disulfide metabolites (collectively) in plasma was developed. After addition of an internal standard and N-ethylmaleimide to the biological samples, excess N-ethylmaleimide and naturally occurring interfering substances were removed by extraction with benzene followed by acidification and extraction with hexane. The N-ethylmaleimide adducts of captopril and of the internal standard were then extracted with benzene and converted to their hexafluoroisopropyl esters.

Captopril: pharmacology, metabolism and disposition.

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent.

Metabolism of captopril-L-cysteine, a captopril metabolite, in rats and dogs.

The metabolism of [14C]captopril-L-cysteine was studied in spontaneously hypertensive rats and pure-bred beagles after a single i.v. dose (4 mg/kg).

Induction of hepatic drug-metabolizing enzymes in rats, dogs, and monkeys after repeated administration of an anti-inflammatory hexahydroindazole.

The effect of repeated administration of an anti-inflammatory hexahydroindazole, (+/-)-3,3 alpha,4,5,6,7-hexahydro-2-[3-(4-morpholinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole (HMPPI), on hepatic microsomal drug-metabolizing enzymes in rats, dogs and monkeys was studied. Dose-dependent increases in the ratio of liver weight to body weight were observed in all three species. Microsomal protein concentration increased in rats and monkeys but not in dogs.

Biotransformation of zeranol: disposition and metabolism in the female rat, rabbit, dog, monkey and man.

The disposition of [3H]zeranol has been studied in the female Wistar rat, New Zealand rabbit, beagle dog, rhesus monkey and man. The blood elimination half-life of total radioactivity in rabbit was 26 h, monkey 18 h and man 22 h. In all species studied the drug was absorbed, oxidized and/or conjugated, and was extensively excreted via the bile in all species except rabbit and man, in which urinary excretion predominated.

Distribution of captopril to foetuses and milk of rats.

1. 14C-Captopril (50 mg/kg) administered orally to pregnant rats resulted in radioactivity passing the placental barrier into foetuses and amniotic fluid. Two hours after dosing, the mean (+/- S.

Renal handling of captopril: effect of probenecid.

14C-Captopril was given intravenously to four normal subjects in a 4-mg priming dose followed by constant intravenous infusion of 1.7 mg/hr for 3.5 hr with and without concomitant probenecid.

Captopril kinetics.

Captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was given by mouth and intravenously in 10-mg doses to five healthy subjects. After intravenous dosing, semilogarithmic plots of captopril blood levels : time showed a triexponential decay. Data were analyzed using an open three-compartment model.

Effect of food on the bioavailability of captopril in healthy subjects.

14C-Captopril was administered as 100-mg tablets to 12 subjects in a two-way crossover study in which subjects were either fasted or were given a standard meal immediately prior to dosing. Based on blood level and urinary excretion data, both the absorption of total radioactivity and the bioavailability of captopril were decreased approximately 35 to 40 per cent after a meal. Whether this moderate decrease in the absorption and the bioavailability of captopril caused by food is of clinical significance has not yet been determined.

Pharmacokinetics of captopril in dogs and monkeys.

[14C]Captopril was given as a priming dose, followed by constant intravenous infusion for 4 or 6 hr, to three anesthetized dogs and three anesthetized monkeys. Blood, urine, and bile samples were collected during and after drug infusion. Pharmacokinetic evaluations were carried out exclusively on data obtained for unchanged captopril.