Disposition of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) in patients with adenocarcinomas.

The pharmacokinetics of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) was investigated in 13 patients with adenocarcinomas who received single intravenous doses ranging from 40 to 250 mg/m2 and in three patients who were administered 1.5 mg/kg every 48 to 72 hours for up to 15 doses. Five patients in the single-dose study also received 100 microCi of [3H]-KS1/4-DAVLB. Overall mean values for the pharmacokinetic variables were as follows: elimination half-life, 31.5 hours; distribution volume, 4.43 L; and clearance, 0.09 L/hr. KS1/4-DAVLB demonstrated linear elimination kinetics in both the single- and multiple-dose studies. Significant concentrations of KS1/4-DAVLB were noted in a pleural effusion. Ten percent of the radioactive dose was recovered in the urine and 20% in the feces over a 5-day period. Small molecular weight vinca species were detected in the feces but not in the serum.

Physiological disposition and metabolism of (3H)bitolterol in man and dog.

The metabolism and disposition of bitolterol, the di-p-toluate ester of N-t-butylarterenol (tBA) was studied in man after a single oral dose and in dog after intraduodenal, iv, or oral administration. The mean (+/- SE) peak plasma radioactivity in man (dose, 70 mug/kg) was 180 +/- 18 ng equivalents of [3H]bitolterol per ml or approximately 11% of the dose, whereas peak plasma radioactivity in dog (dose, 200 mug/kg) was 144 +/- 23 ng equivalents per ml or approximately 4% of the dose. For both man and dog, the time for maximum plasma level of radioactivity varied from 0.5 to 2 hr. In man, only 1% of the plasma radioactivity represented intact [3H]bitolterol 1.0 hr after medication. In the dog, radioactivity was concentrated in lung tissue after iv administration of [3H]bitolterol. Recovery of intact [3H]bitolterol in lung at 4.5 hr ranged from 26 to 46% of total tissue radioactivity after iv dosage and from 4 to 14% total tissue radioactivity after intraduodenal administration. Radioactivity recovered in human urine and feces (0-72 hr) accounted for 86 and 8.1% of the dose, respectively. Recovery of radioactivity in dog urine and feces accounted for 58 and 23% of the dose, respectively, in the same time period. Radiochromatograms of urine samples from man and dog revealed similar patterns of metabolites including free and conjugated forms of both tBA and the 3-O-methyl metabolite, N-t-butylmetarterenol. The major radioactive components of the feces were bitolterol and tBA. The results indicate that bitolterol is absorbed orally and retained as the intact ester in lung. The prolonged bronchodilator activity of bitolterol is due to the slow release of the ester from lung and hydrolysis to tBA, an active beta2-adrenoceptor agonist. Pharmacological activity is terminated by metabolism of tBA via conjugation or 3-O-methylation.

Physiological disposition and metabolism of N-t-butylarterenol and its di-p-toluate ester (bitolterol) in the rat.

The metabolism and disposition of the bronchodilator, N-t-butylarterenol (tBA) and its di-p-toluate ester (bitolterol) were compared in the rat. Radioactivity was preferentially retained in lungs of rats compared with heart and blood after iv medication with tritium-labeled bitolterol, but was not retained in tissues after iv medication with [3H]tBA. After oral and iv medication with [3H]bitolterol, fecal radioactivity accounted for 24% of the dose and 65 and 79% of the radioactivity, respectively, was excreted in urine (0-72 hr). In comparison, urine radioactivity after oral and iv medication with [3H]tBA was 43 and 83% of the dose, respectively, and fecal radioactivity accounted for 43 or 23% of the dose, respectively (0-72 hr). Bitolterol was hydrolyzed in vitro to tBA by esterases found in various tissues including small intestine, liver, and plasma. Moreover, tBA was a substrate for catecholamine O-methyltransferase but not for monoamine oxidase. Similar metabolites were observed in urine samples of rats given either [3H]tBA or [3H]bitolterol. Urine metabolites were identified as free and conjugated forms of both tBA and 3-O-methyl-tBA.

Absorption and disposition of oxarbazole in man and laboratory animals.

Oxarbazole (9-benzoyl-1,2,3,4-tetrahydro-6-methoxycarbazole-3-carboxylic acid) was absorbed by human volunteers, rats, dogs, guinea pigs, and monkeys. In all species of laboratory animals studied, the major urinary metabolite was the product of O-demethylation, 9-benzoyl-1,2,3,4-tetrahydro-6-hydroxycarbazole-3-carboxylic acid; this metabolite was conjugated in all species except the guinea pig. The dog and monkey excreted small quantities of a conjugate of 1,2,3,4-tetrahydro-6-methoxycarbazole-3-carboxylic acid in the urine. Enterohepatic circulation was demonstrated in bile duct-cannulated rats, in which almost 90% of the radioactivity of a dose of 14C-oxarbazole had been excreted into the bile within 24 hr. At the time of peak blood radioactivity, intact oxarbazole was the major constituent circulating in the bloodstream of rats and monkeys that had received 14C-oxarbazole orally. The clearance of either intact oxarbazole in man and guinea pig, or undifferentiated radioactivity in rat, dog, and monkey, did not follow the kinetics of a simple model.

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.

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.