Disposition of a new diacid angiotensin-converting enzyme inhibitor after intravenous administration of drug or prodrug to monkeys and dogs.

The disposition of [4S-[4 alpha,7 alpha,(R*),12b beta]]-7- [S-(1-carboxy-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6- oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid (MDL 27,088), a new a new angiotensin-covering enzyme inhibitor, was studied in cynomolgus monkeys and beagle dogs given intravenous (iv) doses of MDL 27,088 or its prodrug, MDL 27,210. Although in both species iv-administered MDL 27,210 was extensively (> 99.9%) metabolized and excreted in the urine and feces as MDL 27,088, the disposition of MDL 27,088 appeared to be significantly influenced by its mode of administration. For example, the mean terminal half-life of MDL 27,088 in plasma was longer when MDL 27,088 was given as its prodrug (3.65 and 2.23 h in monkeys and dogs, respectively) than when it was administered directly (0.84 and 1.05 h in monkeys and dogs, respectively). The renal excretion of MDL 27,088 also increased (from 33 to 73% of the dose in monkeys and from 9 to 17% of the dose in dogs) when MDL 27,088 was administered directly versus when it was given as its prodrug. These and other results of this study suggest that the disposition of MDL 27,088 can be significantly altered by iv administration of its prodrug form. Such changes in disposition also suggest that iv administration of prodrug may influence the pharmacological activity of MDL 27,088.

Disposition and metabolism of the angiotensin-converting enzyme inhibitor [4S-[4 alpha, 7 alpha, (R*), 12b beta]]-7-[S-(1-ethoxycarbonyl-3- phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid in monkeys and dogs.

[4S-[4 alpha, 7 alpha, (R*),12b beta]]-7-[S- (1-ethoxycarbonyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid (MDL 27,210) is the ethyl ester prodrug of a potent angiotensin-converting enzyme inhibitor, MDL 27,088. After a single dose of [14C]MDL 27,210 (3 mg/kg iv), MDL 27,210 was rapidly eliminated from the plasma of monkeys and dogs with a terminal half-life of approximately 0.3 hr. The steady-state volume of distribution was 0.15 liter/kg in dogs and 0.28 liter/kg in monkeys. Monkeys excreted 52% of the 14C dose in the feces and 41% in the urine; dogs excreted 80% of the 14C dose in the feces and 14% in the urine. The presence of a large fraction of the 14C dose in the feces of both species following iv administration suggests that significant biliary excretion occurred. MDL 27,210 administered iv to monkeys and dogs was rapidly and extensively (greater than 99.9%) metabolized, primarily to its diacid metabolite, MDL 27,088. The half-life of MDL 27,088 was 2.2 hr in dogs and 3.6 hr in monkeys.

Caffeine disposition in the pregnant rabbit. I. Pharmacokinetics following administration by intravenous bolus and continuous zero-order infusion.

We studied the pharmacokinetics of caffeine in the pregnant New Zealand White rabbit, using two methods of drug administration. Ten rabbits that received a continuous intravenous infusion of caffeine (8-22 mg/kg.day) through 29 days of gestation exhibited increased plasma concentrations of caffeine and paraxanthine, its major metabolite, in the last half of gestation. Three rabbits that received intermittent intravenous bolus doses of caffeine (40 mg) exhibited areas under the caffeine plasma concentration versus time curve at 29 days of gestation that were 85-165% greater than those observed before mating. The results of these studies indicate that the elimination of caffeine is diminished in late gestation in the rabbit.

Caffeine disposition in the pregnant rabbit. II. Fetal distribution of caffeine and paraxanthine during chronic maternal caffeine administration.

Twenty-three New Zealand White rabbits received a continuous intravenous infusion of caffeine during gestation. The amniotic fluid/maternal plasma concentration ratio was higher for caffeine than for its major metabolite, paraxanthine, throughout gestation, and increased near term for both compounds. Both compounds distributed nearly homogeneously to fluids and tissues of the 29-day fetus, with mean fetal/maternal concentration ratios of 0.7 for paraxanthine and 0.9 for caffeine. The free fraction of caffeine was constant during gestation (about 0.8), while that of paraxanthine increased from 0.25 to 0.4. Similar results were observed in 3 Dutch Belted rabbits given caffeine in their drinking water and sacrificed at 29 days of gestation.

Caffeine and paraxanthine pharmacokinetics in the rabbit: concentration and product inhibition effects.

The disposition of caffeine (C) and its major metabolite paraxanthine (P) have been determined following i.v. bolus dosing both separately and concomitantly to New Zealand White rabbits. Caffeine clearances of 1.52-6.71 ml/min/kg were observed and were suggestive of polymorphism with rapid (type I) and slow (type II) metabolizing subpopulations represented. Type II metabolizers exhibited dose-independent pharmacokinetics for C, while the clearances of type I animals were dose-dependent (lower clearances at higher doses). The P clearances were not dose-dependent. In type I rabbits coadministration of P inhibited C metabolism by as much as 71%. Results were consistent with the hypothesis that at least two forms of cytochrome "P-450" mediate the metabolism of C in the rabbit.

Improved micro-method for the high-performance liquid chromatographic determination of caffeine and paraxanthine in biological fluids.

A high-performance liquid chromatographic procedure is reported for reproducibly and sensitively quantitating caffeine and its N-demethylated metabolite paraxanthine in microsamples. A 5-micron reversed-phase radial compression column and 214-nm fixed wavelength ultraviolet detector were used to attain a sensitivity sufficient to quantitate these compounds at concentrations as low as 80 ng/ml using only 25 microliter of sample. The assay is applicable to microliter samples of whole blood, serum, plasma, saliva, amniotic, cerebrospinal and gastric fluids such as might be obtained in studies involving small animals or neonates. The utility of the assay is illustrated with caffeine and paraxanthine levels measured in several maternal and fetal fluids following constant-rate intravenous infusion of caffeine into a rabbit throughout pregnancy.

Comparative metabolism of benorylate and an equivalent mixture of aspirin and paracetamol in neonate and adult rabbits.

1. Benorylate was well absorbed in rabbits, but more slowly than an equimolar mixture of aspirin and paracetamol. 2. Benorylate was extensively hydrolysed and converted to the typical metabolites of aspirin and paracetamol by both neonate and mature rabbits. 3. Absorption of either aspirin-paracetamol or benorylate was slower in neonate rabbits than in adult rabbits. 4. The excretion rate in adult rabbits was faster, for both aspirin and paracetamol metabolites, than in neonate rabbits.