Chronological Effects of Rifampicin Discontinuation on Cytochrome P450 Activity in Healthy Japanese Volunteers, Using the Cocktail Method

Abstract

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.

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

“…According to the model, the induction of the hydroxylation of BRV to BRV-OH accounts for the observed decrease in the acid BRV-AC formation. The higher induction effect of rifampin on the CYP2C19-mediated reaction over CYP2C9 is consistent with previous in vitro hepatocyte data (Raucy et al, 2002;Madan et al, 2003;Paris et al, 2009), as well as reported clinical interaction studies (Inui et al, 2013). Of interest, when tested in vitro, rifampin induces both CYP2C9 and CYP2C19 mRNA, with a somewhat larger effect on the former (Yajima et al, 2014).…”

Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists

“…These results are consistent with in vivo studies using cultured human hepatocytes, where a period of 14 days was found to be sufficient for enzyme function to return to baseline levels after rifampicin removal 4. On the other hand, Inui et al reported a period of 8 days for CYP3A activity to recover after rifampicin withdrawal in healthy subjects 5. The time span required for deinduction may be variable.…”

Population Pharmacokinetics of Rifampicin in Chinese Patients With Pulmonary Tuberculosis

“…Its bacterial pathogen, Mycobacterium tuberculosis (MTB), infects almost 33% of the global population, and rifampicin (RIF) is a first‐line anti‐TB drug based on its efficacy. RIF induces various cytochrome P450 (CYP) isoforms, namely 3A4, 2C9, and 2C19, which can catalyze the metabolism of drugs, including RIF. Previous research studies have indicated that low serum RIF levels are common in TB patients.…”