Pharmacokinetics and pharmacodynamics of bromocriptine in the rat.

The absorption, distribution, and excretion of bromocriptine were studied following oral and parenteral administration of non-radioactive and 14C-labelled drug in the rat. Total radioactivity was measured in blood, tissues, and excreta by liquid scintillation counting while the parent drug was determined in plasma and selected tissues by radioimmunoassay. The pharmacokinetic observations were compared with the time course of drug-induced hypothermia in cold-room acclimatized rats. The results indicated that oral doses of bromocriptine were rapidly, though incompletely (32-40 per cent), absorbed, but underwent extensive first-pass metabolism, resulting in an absolute bioavailability of only 6 per cent. The bioavailability increased to approximately 22 per cent in rats pretreated with the hepatic microsome inhibitor proadifen, thus suggesting the liver as the principal site of biotransformation. Absorbed bromocriptine showed preferential distribution into the tissues, although no apparent accumulation of drug-related material occurred in the body. The drug was eliminated almost exclusively by metabolism and biliary excretion into the faeces. Comparison of the pharmacodynamic and the pharmacokinetic profiles indicated a dose relationship between hypothermia and plasma bromocriptine concentrations but not total radioactivity levels. The hypothermic response was also intensified by proadifen pretreatment, thus confirming the parent drug as the pharmacologically active entity. It is believed that the previously reported delay in the onset of bromocriptine activity is not pharmacokinetic in nature, but is related to the properties of the receptors at the target site or to the pharmacologic events that result in the observed effects.

The biotransformation of fluproquazone in man and several animal species.

The biotransformation of 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) has been investigated in man, mouse, rat, rabbit, and dog. Single oral doses of 3H-fluproquazone were administered to the animals (15 mg/kg). Human volunteers received 100 mg 3H-fluproquazone t.i.d. for 5 days (3.8 mg/kg). Two potential metabolites were synthesized: 4-(p-fluorophenyl)-1,2-dihydro-1-isopropyl-2-oxo-7-quinazolinecarboxylic acid (4) and 4-(p-fluorophenyl)-7-hydroxymethyl-1-isopropyl-2(1H)-quinazolinone (11). The human urinary metabolites of fluproquazone were separated and purified by a combination of extractions and liquid chromatography on reversed-phase columns, and structures were proposed on the basis of identify with known standards, mass spectral data, and retention time comparison. Definitive structures were assigned to five metabolites. Fluproquazone and its metabolites were characterized and quantitated in the blood, urine, and feces of man, mouse, rat, rabbit, and dog by high-pressure liquid chromatography coupled to a radioactivity monitor or by reverse isotope dilution analysis. Significant quantities of fluproquazone were noted in the blood of all species. The major circulating metabolite in blood at or near the peak of radioactivity was 11 in rat, mouse, and dog and 4 in man and rabbit. In all species analyzed, 4 was the major metabolite excreted in the urine and feces. In man the minor metabolites consisted of 11 as a conjugate and several phenolic derivatives also conjugated. The animals were exposed to the same major metabolite as man and each minor metabolite found in man, with the exception of a few very minor ones, was identified in at least one of the animal species. The metabolite pattern did not vary significantly among the 3 human subjects analyzed nor over the 5-day dosing period. Two biotransformation pathways were identified. The major pathway was sequential oxidation with or without conjugation of the 7-methyl group; aromatic hydroxylation and conjugation was a minor pathway.

Influence of various anions on intestinal disappearance of hexamethonium chloride and pralidoxime chloride in rats.

The intestinal transfer of two poorly absorbed quaternary ammonium drugs, hexamethonium chloride (I) and pralidoxime chloride (II), in the presence of various organic and inorganic anions was investigated in the rat using a modified in situ gut technique. The results were in agreement with those of the conventional in situ loop and plasms drug level techniques. Of the anions investigated, cholate, desoxycholate, taurocholate, phoscholate, dehydrocholate, and hyodesoxycholate had the greatest effect on increasing the amount and rate of disappearance of I. Similarly, the amount and rate of disappearance of II were enhanced markedly in the presence of phoscholate and trichloroacetate. The effect of cholate and phoscholate was investigated in detail. The membrane permeability and histological studies indicated that these anions may compromise the structural integrity of the membrane tissue, thus enhancing drug transfer.

Metabolism of butalbital, 5-allyl-5-isobutylbarbituric acid, in the dog.

Butalbital, 5-allyl-5-isobutylbarbituric acid, labeled in the 2-position with 14C, was administered to dogs. Ninety-two percent of the radioactivity of the dose was excreted in the urine. The drug and three major urinary metabolites were identified in the urinary excretion of the dog. The major metabolite was 5-isobutyl-5-(2,3-dihydroxypropyl)barbituric acid, which accounted for 50.2% of the dose. Smaller amounts of the unchanged drug (2.6% of the dose) and urea (8.6% of the dose) were present. 5-Allyl-5-(3-hydroxy-2-methyl-1-propyl)barbituric acid, formed by omega-hydroxylation, accounted for 10.1% of the dose; the optical rotation of the 1,3-diethyl derivative was [alpha]D20 = +10.5. Five minor and unidentified metabolities accounted for an additional 10.7% of the dose. A total of 82.2% of the dose was accounted for.