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Introduction: The absorption process is an essential stage that determines the bioavailability of xenobiotics during extravascular administration. The intensity of absorption depends on numerous factors not necessarily related to the substance and its formulation, and also on biotransformation and active transport processes. Methanol and its water solutions facilitate the animal dosage of several drugs, inhibitors and other xenobiotics in a soluble form while these compounds are not soluble in water. However, during administration of small amounts of drugs, the effect of vehiculum on drug fate in the body becomes also evident. Material and Methods: The study was performed on male Wistar rats cmd(WI)WU. Phenacetin was given per os in a single dose of 100 mg/kg b.w. Various procedures of phenacetin administration were tested, including solubilization in methanol and/or suspension in 1% water solution of carboxymethylcellulose. A three-hour pretreatment with 75% methanol solution before phenacetin administration was also applied. Serum concentrations of phenacetin and acetaminophen, its metabolite, were determined by HPLC method with solid phase extraction. Results and Conclusions: The presented results indicate that methanol decreases blood acetaminophen concentrations and phenacetin bioavailability. These changes appeared immediately after methanol exposure, but during the last four weeks of the experiment, when methanol was not in use, and only phenacetin in 1% carboxymethylcellulose was administered to rats, the decrease in phenacetin biotransformation and bioavailability was maintained. [ABSTRACT FROM AUTHOR]

Several forms of cytochrome P-450 (CYP) metabolize R,S-warfarin in a regio- and enantioselective manner, therefore R,S-warfarin can be recognized as a metabolic probe for a number of CYP isoforms. We have applied a warfarin model in vivo in order to estimate the inhibitory properties of 5- and 8-methoxypsoralens on the activity of rat CYP isoforms. The area under the serum concentration versus time curve (AUC) values from time zero to 5 h for R- and S-warfarin and their metabolites were calculated. R,S-Warfarin kinetics measurements were made three times on each rat: a week before the 7-days inhibitor treatment, 3 h after the last dose of inhibitor and 3-7 days after the inhibitor was withdrawn. The inhibitory effect of cimetidine on CYP 2C11 and CYP 2C6 activities was confirmed in this approach and can be recognized as a positive control in validation of the in vivo experiment. Both 5- and 8-methoxypsoralen inhibited CYP 2C6 activity as the respective AUC for metabolite/warfarin enantiomer ratio decreased significantly. The activity of CYP 2C6 in 5- and 8-methoxypsoralen-treated rats increased over control values after the inhibitor was withdrawn. It was also observed that cimetidine additionally inhibits the absorption of R,S-warfarin and a decrease in the sum of AUC for R- and S-enantiomers became evident in spite of inhibition of the activity of both CYPs. 5-Methoxypsoralen modified the serum R-warfarin/S-warfarin ratio and a selective increase in AUC(S-warfarin) was observed, the most pronounced being after the inhibitor was withdrawn. This effect is not likely to be mediated by P-glycoprotein (P-gp) because quinidine--, a P-gp inhibitor at a dose of 15 mg kg(-1) body wt.--did not influence the AUC for either enantiomer., (Copyright 2002 John Wiley & Sons, Ltd.)