1. 14C-labelled 1-aminobenzotriazole (ABT), a suicide inactivator of cytochrome P450, was synthesized and administered orally to male rats. The rats were killed at 1, 6, 24, 48 or 72 h after dosing and the concentration of total radioactivity in various tissues and organs measured. 2. The compound appears to be absorbed slowly with 50% of the radioactivity remaining in the stomach at 6 h after dosing and maximum plasma and tissue concentrations were observed at 24 h. 3. Approximately 71% of the dose of 14C was excreted in the urine and 12% in the faeces over 72 h, indicating oral absorption of at least 71%. Tissue-to-plasma ratios of 14C were highest in the liver, adrenals and kidneys, which all contain significant amounts of cytochrome P450; the half-lives of elimination for total 14C in liver, adrenals and kidneys were approximately 24, 16 and 12 h, respectively, while the half-life in plasma was approximately 9 h. 4. ABT was metabolized by N-acetylation, with the acetylated product attaining concentrations equal to ABT in the plasma; two other major metabolites were also excreted in the urine namely, the N-glucuronide of 1-aminobenzotriazole and the N-glucuronide of benzotriazole.
Ten healthy volunteers were used in two studies investigating the effect of short-term Brassica consumption on caffeine metabolism. In the first study volunteers were given three Brassica-containing meals, the last one 3 h prior to caffeine administration. In the second study volunteers were given two Brassica-containing meals and then fasted overnight before caffeine administration. In both studies the mean plasma half-life of caffeine was reduced by approximately 20% following a Brassica diet, suggesting that Brassica vegetables stimulate caffeine metabolism. When caffeine was given 3 h after the last meal, plasma caffeine concentrations over 6 h, were increased by up to 27% on the Brassica diet compared to controls. This may be due to a transient increased permeability of the intestine to caffeine, immediately following Brassica consumption. This effect was not seen in the second study where there was a 12-h period between the last meal and caffeine administration. There was large interindividual variation in the effect of the Brassica diet on caffeine metabolism.
1. The metabolism of acitretin and its 13-cis isomer, isoacitretin, has been investigated in the in situ isolated perfused rat liver in order to differentiate the action of the liver from that of the gut on the metabolism of these isomers. 2. Acitretin undergoes alpha-oxidation, chain shortening O-demethylation, and glucuronidation in the perfused rat liver. 3. Isoacitretin undergoes glucuronidation as the major, almost exclusive, route of metabolism in the perfused rat liver. 4. The difference in the hepatic metabolism of the cis and trans isomers of this retinoid may explain the differences in their pharmacokinetics, and may help in understanding the pharmacokinetics of related retinoids.
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