Effect of rifampicin on pravastatin pharmacokinetics in healthy subjects.

AIMS Previous work has shown that rifampicin, a potent inducer of several cytochrome P450 (CYP) enzymes and transporters, decreased the plasma concentrations of simvastatin acid by more than 90%. This study was conducted to investigate the effect of rifampicin on the pharmacokinetics of pravastatin. METHODS In a randomised, cross-over two-phase study with a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 40 mg dose of pravastatin was administered orally. Plasma concentrations of pravastatin were measured up to 12 h by a sensitive LC-MS-MS method. RESULTS During the rifampicin phase, the mean total area under the plasma concentration-time curve of pravastatin [AUC(0-infinity )] was 69% (range 24-220%) of the corresponding value during the placebo phase (P < 0.05, 95% confidence interval for the difference -51.9 - -0.4 ng ml-1.h). In five of the 10 subjects the AUC(0-infinity ) of pravastatin during the rifampicin phase was 50% or less of that during the placebo phase. Rifampicin had no significant effect on the peak concentration, elimination half-life or renal clearance of pravastatin. CONCLUSIONS Rifampicin caused a statistically significant decrease in the plasma concentration of pravastatin given as a single oral dose to healthy subjects. However, the effect of rifampicin varied greatly between subjects. The mean rifampicin-induced decrease in pravastatin concentration was considerably smaller than that observed previously for simvastatin.

[1]  J. Lehmann,et al.  The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. , 1998, The Journal of clinical investigation.

[2]  A. Peyer,et al.  HMG‐CoA reductase inhibitors and P‐glycoprotein modulation , 2001, British journal of pharmacology.

[3]  H L Pearce,et al.  Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. , 1988, Molecular pharmacology.

[4]  V. Sasseville,et al.  A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2) , 1999, The Journal of Biological Chemistry.

[5]  P. Neuvonen,et al.  Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole , 1998, Clinical pharmacology and therapeutics.

[6]  H K Kroemer,et al.  The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. , 1999, The Journal of clinical investigation.

[7]  G. Sandusky,et al.  Expression of multidrug resistance‐associated protein 2 (MRP2) in normal human tissues and carcinomas using tissue microarrays , 2002, Histopathology.

[8]  G. Ecker,et al.  Structure-activity-relationship studies on modulators of the multidrug transporter P-glycoprotein--an overview. , 1995, Wiener klinische Wochenschrift.

[9]  U. Christians,et al.  Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[10]  U. Christians,et al.  Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin. , 1999, The Journal of pharmacology and experimental therapeutics.

[11]  J. Lehmann,et al.  An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway , 1998, Cell.

[12]  M. Jemal,et al.  Quantitative determination of pravastatin and its biotransformation products in human serum by turbo ion spray LC/MS/MS. , 2000, Journal of pharmaceutical and biomedical analysis.

[13]  S. Singhvi,et al.  Biotransformation of pravastatin sodium in humans. , 1991, Drug metabolism and disposition: the biological fate of chemicals.

[14]  R. Kim,et al.  Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation , 2003, Journal of Pharmacology and Experimental Therapeutics.

[15]  C. Fichtenbaum,et al.  Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047 , 2002, AIDS.

[16]  U. Hofmann,et al.  Enzyme induction in the elderly: Effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone , 2000, Clinical pharmacology and therapeutics.

[17]  A. Fujimura,et al.  Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin , 2001, Clinical pharmacology and therapeutics.

[18]  M. Fromm,et al.  The effect of rifampin treatment on intestinal expression of human MRP transporters. , 2000, The American journal of pathology.

[19]  S. Vavricka,et al.  Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver , 2002, Hepatology.

[20]  Y. Sugiyama,et al.  Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[21]  P. Neuvonen,et al.  Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid , 1996, Clinical pharmacology and therapeutics.

[22]  J. Derancourt,et al.  Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. , 1989, Drug metabolism and disposition: the biological fate of chemicals.

[23]  L. Jokubaitis.  Updated clinical safety experience with fluvastatin. , 1994, The American journal of cardiology.

[24]  C. Wolf,et al.  The effects of inducing agents on cytochrome P450 and UDP-glucuronyltransferase activities in human HEPG2 hepatoma cells. , 1993, Biochemical pharmacology.

[25]  J. Kolars,et al.  Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. , 1992, The Journal of clinical investigation.

[26]  P. Neuvonen,et al.  Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations , 2000, Clinical pharmacology and therapeutics.

[27]  R. Kim,et al.  Pharmacogenomics of organic anion-transporting polypeptides (OATP). , 2002, Advanced drug delivery reviews.

[28]  B. Pentland,et al.  Effects of microsomal enzyme induction on paracetamol metabolism in man. , 1981, British journal of clinical pharmacology.

[29]  V. Fischer,et al.  The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[30]  B. Arison,et al.  In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[31]  Mikko Niemi,et al.  Pharmacokinetic Interactions with Rifampicin , 2003, Clinical pharmacokinetics.