Pharmacokinetic Interactions with Rifampicin

Abstract

The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. Full induction of drug-metabolising enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing rifampicin. Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein. Thus, for example, oral midazolam, triazolam, simvastatin, verapamil and most dihydropyridine calcium channel antagonists are ineffective during rifampicin treatment. The plasma concentrations of several anti-infectives, such as the antimycotics itraconazole and ketoconazole and the HIV protease inhibitors indinavir, nelfinavir and saquinavir, are also greatly reduced by rifampicin. The use of rifampicin with these HIV protease inhibitors is contraindicated to avoid treatment failures. Rifampicin can cause acute transplant rejection in patients treated with immunosuppressive drugs, such as cyclosporin. In addition, rifampicin reduces the plasma concentrations of methadone, leading to symptoms of opioid withdrawal in most patients. Rifampicin also induces CYP2C-mediated metabolism and thus reduces the plasma concentrations of, for example, the CYP2C9 substrate (S)-warfarin and the sulfonylurea antidiabetic drugs. In addition, rifampicin can reduce the plasma concentrations of drugs that are not metabolised (e.g. digoxin) by inducing drug transporters such as P-glycoprotein. Thus, the effects of rifampicin on drug metabolism and transport are broad and of established clinical significance. Potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment. It is particularly important to remember that the concentrations of many of the other drugs used by the patient will increase when rifampicin is discontinued as the induction starts to wear off.

The Effect of P-Glycoprotein Inhibition and Activation on the Absorption and Serum Levels of Cyclosporine and Tacrolimus in Rats

“…Verapamil, which increased the intestinal absorption of cyclosporine and tacrolimus in this study, has previously been reported to be a substrate of P-gp when used in low doses and to strongly inhibit P-gp when used high doses [8]. Furthermore, it has been suggested that rifampicin activates P-gp in vivo and in vitro [11,12]. Although there are some other studies about the effects of P-glycoprotein modulation on the bioavailability of several drugs [16][17][18], to best of the authors' knowledge, this is the first study to investigate the effects of P-gp-inhibiting and -activating drugs on the intestinal absorption of immunosuppressive drugs.…”

“…On the other hand, P-gp can easily be activated by some agents, such as rifampicin [11,12]. P-glycoprotein plays an important role in the intestinal absorption of immunosupressive agents, including cyclosporine and tacrolimus [13][14][15].…”

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non‐peptide AVP antagonist in healthy subjects

“…In comparison, when 6 mg midazolam was given orally with 200 mg ketoconazole, midazolam Cmax and AUC(0,•) were increased 4-fold and 13.6-fold compared with midazolam alone [13]. When oral midazolam was given with rifampicin at steady-state, the midazolam AUC was decreased 96-98% [11].…”

“…On day 9, tolvaptan 240 mg and rifampicin 600 mg were simultaneously administered to subjects in the fasted state. Rifampicin administration has been reported to decrease the concentrations of weak CYP3A4 substrates such as midazolam by 96-98% [11].…”

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

“…90,91 It was recently reported that concomitant administration of rifampin at a dose of 600 mg/day for 10 days in healthy volunteers reduced digoxin plasma concentrations substantially after an oral single-dose (1 mg) administration compared with the plasma-time profile without rifampin treatment. 92 The effect was less pronounced after intravenous administration of digoxin.…”