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J W Cox

Publications and source records attributed to J W Cox.

96 records · Page 6Linked to original sources
PubMedDate not supplied

Pharmacokinetic interactions between arbaprostil and aspirin in humans.

Arbaprostil is an orally active prostaglandin E2 analogue. It has been developed as a drug to treat ulcers induced by non-steroidal anti-inflammatory drugs. In this study, pharmacokinetic interactions between arbaprostil and aspirin were examined in humans after chronic doses of both drugs. Subjects received either arbaprostil (50 micrograms), aspirin (975 mg) or arbaprostil (50 micrograms) and aspirin (975 mg) four times a day for 6 days and one dose on 7th day. Blood and urine samples were collected after the last dose for 6 h. Pharmacokinetic parameters of arbaprostil, aspirin, and salicylate were determined. Coadministration of arbaprostil significantly lowered the area under curve (5.09 +/- 0.32 micrograms hml-1 vs 5.78 +/- 0.29 micrograms hml-1, mean +/- SE, p less than 0.05) and time (0.45 +/- 0.07 h vs 0.70 +/- 0.12 h, p less than 0.05) to reach maximal plasma concentration of aspirin (acetylsalicylate). The pharmacokinetics of salicylate were not changed by arbaprostil, nor were the pharmacokinetics of arbaprostil affected by aspirin. Coadministration of these two drugs did not appear to potentiate the side-effects of either drug. The results suggest that arbaprostil and aspirin may be administered together without clinically significant changes in pharmacokinetics or adverse side-effects.

Adult↗
PubMedDate not supplied

Distribution and disposition of trospectomycin sulfate in the in vivo rat, perfused rat liver, and cultured rat hepatocytes.

Trospectomycin sulfate is an experimental, aminocyclitol antibiotic. It has been shown in preclinical, chronic safety studies in the dog and rat to elicit a reversible, lysosomal phospholipidosis in liver. The present experiments were conducted to characterize the tissue distribution and disposition of 3H]trospectomycin sulfate in the male rat, perfused rat, perfused rat liver, and cultured rat hepatocytes. Following a 5 mg/kg iv dose to four rats, approximately 70% of the dose was recovered within 24 hr primarily in urine as unchanged drug, and the remainder was eliminated with a terminal phase half-life in blood and tissues of 3 days. Fecal excretion was relatively minor (16% of the dose recovered in feces in 7 days) until later timepoints, when it was the principal pathway of terminal phase elimination. The liver sequestered approximately 10% of the dose and had the highest tissue levels of drug at all times measured. Liver perfusion experiments indicated that trospectomycin accumulated in a hepatic depot compartment as parent drug by a first-order process which was nonsaturable up to a 1 mM concentration of drug. Biliary excretion of unchanged trospectomycin by the perfused liver was slow (approximately 3% of the dose in 2 hr) and occurred by both paracellular and transcellular mechanisms. The hepatic depot compartment appeared to be responsible for transcellular biliary excretion, and thus for the sustained fecal excretion observed in vivo. Subcellular distribution experiments indicated that at least 50% of the drug in the hepatic depot was sequestered in organelles having a broad density range. The existence of a trospectomycin depot compartment was also demonstrated in cultured hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Pharmacokinetics and excretion of the 21-aminosteroid antioxidant U-74006F in rat and perfused rat liver.

U-74006F, 21-(4-(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl)-16 alpha-methylpregan-1,4,9(11)-triene monomethane sulfonate, is currently under development for the treatment of human central nervous system trauma and ischemia. The iv pharmacokinetics and excretion of 14CU-74006F (labeled in the 16 alpha-methyl group) and 3HU-74006F (labeled in a pyrrolidine ring) were investigated in the young adult Sprague-Dawley rat and the perfused rat liver. Following a 3 mg/kg iv bolus dose, plasma levels of 14CU-74006F declined biexponentially with alpha and beta half-times of 8 and 70 min, respectively. The terminal phase volume of distribution was 5.1 liters/kg and the plasma clearance was 51 ml/min/kg, which is similar to the in vivo hepatic plasma flow. Plasma levels of total 14C-labeled metabolites quickly exceeded levels of parent drug and declined with a terminal phase half-time of 50 hr. Greater than 90% of the 14C and 3H doses was excreted in feces with terminal phase half-times of 107 and 46 hr, respectively. Consistent with high hepatic clearance, the oral solution bioavailability of U-74006F was 16%, and the hepatic extraction efficiency of U-74006F from 3% bovine serum albumin (w/v) medium in the perfused liver was 80-86% under nonsaturating conditions at physiological flows. U-74006F was rapidly metabolized in the perfused liver and excreted in bile as metabolites. The biliary excretion mechanism was more easily saturated than hepatic uptake and metabolism, with the consequence that, at pharmacologically relevant perfusate levels of drug, metabolites accumulated in the liver and effluxed into the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗