The mechanism of the warfarin-rifampin drug interaction in humans

The mechanism of the drug interaction in humans between warfarin and rifampin was investigated by monitoring the elimination kinetics and metabolic disposition of a single oral dose of pseudoracemic warfarin by GC/MS. The decrease in hypoprothrombinemia observed with concomitant administration of therapeutic doses of rifampin was accompanied by a substantial decrease in the elimination half-lives of both warfarin enantiomers. Rifampin increased the clearance of (R)-warfarin threefold and the clearance of (S)-warfarin twofold. The excretion profiles for warfarin and its metabolites in urine and feces were similar for both control and treated subjects with the exception that 4'-hydroxywarfarin (stereoselective for the (S)-enantiomer) was observed when rifampin was administered. 4'-Hydroxywarfarin is a metabolite of the drug hitherto undetected in vivo in humans. Based on formation clearance values estimated for 6-, 7-, and 8-hydroxywarfarin, rifampin appears to increase the clearance of the parent drug by induction of the cytochrome P-450 isozyme(s) responsible for aromatic hydroxylation.     

Biopharmaceutic factors that influence effects of anticholinergic drugs: comparison of propantheline, hexocyclium, and isopropamide.

The antisecretory (determined from salivary flow rates) and antimotility (determined from riboflavin absorption) effects of usually recommended doses of propantheline, hexocyclium, and isopropamide were compared in four adult volunteers. Both propantheline and hexocyclium significantly decreased salivary flow and increased riboflavin absorption. Although the usual dose of propantheline was about twice as effective as the usual dose of hexocyclium in suppressing salivary flow, these doses produced comparable effects on riboflavin absorption. Isopropamide had little or no effect on either the salivary flow rate or riboflavin absorption. Propantheline and hexocyclium elicited little effect on salivary flow when administered after a meal. Prolonged-release dosage forms of these drugs produced effects comparable to those produced by much smaller doses in conventional tablets and gave no indication of providing prolonged anticholinergic effects.     

A model for the prospective identification of the prenephrotoxic state during gentamicin therapy

A computer method has been investigated to differentiate the prenephrotoxic patient from the nontoxic patient by routine monitoring of serum gentamicin concentrations duringtherapy, without the need to discontinue medication. The method deliberately assumes an incorreect pharmacokinetic model and uses a nonlinear regression program to analyze data collected during continuous dosing. In principle, it appears that the prenephrotoxic patients may be identified on the basis of a decreasing apparent elimination rate constant of gentamicin during continuous therapy.This work was supported in part by Grant No. GM-20852 from the National Institutes of Health.