rifampin and 1-7-dimethylxanthine

Cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A are major factors involved in the metabolism of clinically prescribed drugs. Because the time course after drug treatment discontinuation has received little attention, we aimed to clarify the chronological changes of rifampicin-induced CYP enzyme activities after rifampicin discontinuation. Thirteen volunteers took 450 mg of rifampicin once daily, and the cocktail method, which uses caffeine, losartan, omeprazole, dextromethorphan, and midazolam as CYP-specific probes, was repeatedly used for the evaluation of CYP levels. Concentrations of probes and metabolites were determined by liquid chromatography-tandem mass spectrometry. Seven-day rifampicin administration increased CYP2C19 and CYP3A enzyme activities. The induced CYP2C19 and CYP3A activities remained elevated at 4 days after rifampicin discontinuation and returned to baseline levels 8 days after rifampicin discontinuation. CYP1A2 and CYP2D6 enzyme activities showed no significant changes, and CYP2C9 enzyme activity was increased with rifampicin administration, with a tendency toward statistical significance. Drug interactions can occur even after rifampicin discontinuation.

Topics: Adult; Antibiotics, Antitubercular; Asian People; Caffeine; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Humans; Imidazoles; Losartan; Male; Midazolam; Omeprazole; Rifampin; Tetrazoles; Theophylline; Time Factors; Withholding Treatment

The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize drug action, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. However, selectivity of action has been poorly characterized in vivo.. This study investigated the effect of 3 and 28 days of treatment with quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase in 28 healthy young male volunteers divided into three groups with a cocktail of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and dapsone.. Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. Rifampin showed evidence of time-dependent induction of the activities of all measured oxidative routes of metabolism but decreased the acetylation ratio in fast acetylators. The quinidine/rifampin combination resulted in selective CYP2D6 inhibition and induction of all other enzymes evaluated over this time period, suggesting that predictable complex interactions occur with the drug combination.. These observations illustrate the value of simultaneous assessment of the effect of modulators on the activities of multiple specific enzymes with the drug cocktail approach.

Topics: Acetylation; Administration, Oral; Adrenergic alpha-Antagonists; Adult; Anti-Arrhythmia Agents; Antibiotics, Antitubercular; Anticonvulsants; Aryl Hydrocarbon Hydroxylases; Caffeine; Central Nervous System Stimulants; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dapsone; Debrisoquin; Drug Administration Schedule; Enzyme Inhibitors; Humans; Male; Mephenytoin; Mixed Function Oxygenases; Quinidine; Reference Values; Rifampin; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Theophylline