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LETTERS TO THE EDITOR

Response to Comments on "Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems"

Department of Biopharmaceutical Sciences, University of California, San Francisco, CA

Received December 5, 2005; accepted December 14, 2005.

Dr. Kivistö's comments relate not to the model compound aspects of rifampicin but rather to its effects when dosed to patients. Upon continuing dosing, its up-regulation of enzyme levels, P-glycoprotein, and MRP2 are well known. In fact, our early studies investigating the effects of multipledose rifampicin on cyclosporine (Hebert et al., 1992; Wu et al., 1995) could not be explained only by hepatic metabolism of cyclosporine and led us to our initial hypothesis concerning the importance of CYP3A4 and P-glycoprotein interplay in the intestine in explaining the marked decrease in cyclosporine blood levels with concomitant, multiple dosing of rifampicin. Future publications from our laboratory will demonstrate that our in vitro and isolated perfused rat liver studies with rifampicin and atorvastatin are relevant to dosing of these two drugs in whole animal studies and in humans. We have recently completed single-dose pharmacokinetic studies of this interaction in rats and humans, where atorvastatin is dosed orally and rifampicin intravenously, showing that the effects noted in the acute studies here are also significant in animals and humans (unpublished data).

Even though we use rifampicin as a model transporter inhibitor, we believe that Dr. Kivistö will recognize that his statement that "such findings are not relevant to continuous drug treatment in clinical practice" may not necessarily be true. A relevant example is the clinical study of Bidstrup et al. (2004), which evaluates the effects of rifampicin on the metabolism of repaglinide. When rifampicin was dosed for 7 days and repaglinide was dosed concomitantly on day 7, a 50% reduction of median repaglinide area under the curve (AUC) was observed compared with a single dose of repaglinide in the absence of rifampicin. However, when repaglinide was dosed on day 8, following 7 days of dosing of rifampicin (when rifampicin was no longer present in the plasma), the authors found "an almost 80% reduction of median repaglinide AUC." The authors suggest that this may be related to rifampin as both an inducer and inhibitor of the metabolism of repaglinide. Most recently, Kajosaari et al. (2005) confirmed this enzyme inhibitory effect of rifampicin in hepatic microsome studies. With such microsomal studies, no potential transporter effects would be evaluated, as we have demonstrated (Lam and Benet, 2004). We hypothesize that a further potential reason that the effect observed on day 7 dosing of repaglinide with rifampicin was significantly less than observed on day 8 dosing of repaglinide (when rifampicin was not present) may be due to rifampicin's ability to inhibit the hepatic uptake of repaglinide during the day 7 studies. We suspect that a number of rifampicin interaction studies may be compromised by concomitant dosing of rifampicin on the day of study of the interacting drug. Thus, it is clinically important to understand all of the potential inductive and inhibitory effects that an interactive drug may have on both enzymatic and transporter processes if one is to correctly characterize and understand the potential for and extent of drug-drug interactions.

Footnotes

doi:10.1124/jpet.105.099473.

ABBREVIATIONS: OATP, organic anion-transporting polypeptide; AUC, area under the curve.

Address correspondence to: Dr. Leslie Z. Benet, University of California San Francisco, 533 Parnassus, Room U-68, San Francisco, CA 94143-0446. E-mail: benet{at}itsa.ucsf.edu

References

Bidstrup TB, Stilling N, Damkier P, Scharling B, Thomsen MS, and Brøsen K (2004) Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. Eur J Clin Pharmacol 60: 109–114.[CrossRef][Medline]

Hebert MF, Roberts JP, Prueksaritanont T, and Benet LZ (1992) Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 52: 453–457.[Medline]

Kajosaari LI, Laitila J, Neuvonen PJ, and Backman JT (2005) Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol 97: 249–256.[CrossRef][Medline]

Lam JL and Benet LZ (2004) Hepatic microsome studies are insufficient to characterize in vivo metabolic clearance and metabolic drug-drug interactions: studies of digoxin metabolism in primary rat hepatocytes versus microsomes. Drug Metab Dispos 32: 1311–1316.[Abstract/Free Full Text]

Lau YY, Okochi H, Huang Y, and Benet LZ (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther 316: 762–771.[Abstract/Free Full Text]

Wu C-Y, Benet LZ, Hebert MF, Gupta SK, Rowland M, Gomez DY, and Wacher VJ (1995) Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 58: 492–497.[CrossRef][Medline]

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