We thank Dr. Kivistö for his comments related to our recent study (Lau et al., 2006) and for giving us a further opportunity to emphasize the importance of understanding transporter-enzyme interplay. Our study and our prior work referenced therein are directed at pointing out that drug-drug interactions resulting in inhibition or induction of both uptake and efflux transporters can result in changes in drug metabolism, even when enzyme levels and activity are unchanged by the interacting drug. We use rifampicin as a general inhibitor of hepatic OATP uptake transporters because it is a drug that we can dose to humans both via the intravenous and oral route and because it differentiates drug interactions related to uptake transporters in the liver and gut from interactions related to enzymatic processes and efflux transporters. Thus, it is a model OATP inhibitor, but we must also quantitate its inhibitory effects on enzyme levels and efflux transporters as we did in the study in question.
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intravenously, showing that the effects noted in the acute studies here are also significant in animals and humans (unpublished data).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.
- Received December 5, 2005.
- Accepted December 14, 2005.
ABBREVIATIONS: OATP, organic anion-transporting polypeptide; AUC, area under the curve.
- The American Society for Pharmacology and Experimental Therapeutics