title: Comparative Evaluation of Dehydroepiandrosterone Sulfate Potential to Predict Hepatic Organic Anion Transporting Polypeptide Transporter-Based Drug-Drug Interactions.
abstract: Pharmacokinetic drug-drug interactions (DDIs) on hepatic organic anion transporting polypeptides (OATPs) are important clinical issues. Previously, we reported that plasma dehydroepiandrosterone sulfate (DHEAS) could serve as an endogenous probe to predict OATP-based DDIs in monkeys using rifampicin as an OATP inhibitor. Since the contribution of hepatic OATPs to the changes in plasma DHEAS by rifampicin remains unclear, however, we performed an in vivo pharmacokinetic study to explore this issue. Since plasma DHEAS concentrations were low in our rat model, the disposition of externally administered DHEAS was evaluated. Intravenously administered DHEAS was recovered mainly in bile (29.1%) and less in urine (2.95%). The liver tissue-to-plasma concentration ratio (Kpliver) decreased from 41.8 to 5.07 by rifampicin, and this decrement was consistent with the decrease in distribution volume from 247 to 59 ml/rat. Comparison of the in vitro IC50of rifampicin for DHEAS uptake by isolated rat hepatocytes and in vivo plasma rifampicin concentration suggested that the effect of rifampicin on the plasma DHEAS concentration was explained mostly by the inhibition of hepatic OATPs, demonstrating that DHEAS could be a biomarker of hepatic OATP activity. Next, previously reported rifampicin-induced changes in plasma concentrations evaluated as an AUC ratio (AUCR) of possible probe compounds were compared on the basis of rifampicin dose/body surface area. The AUCR values of endogenous compounds and i.v. administered statins, for which possible DDIs in the intestinal absorption process can be excluded, increased proportionally to the rifampicin dose. Simultaneous measurement of these endogenous compounds could be effective biomarkers for the prediction of OATP-based DDIs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences University, Kanazawa, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nishizawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences University, Kanazawa, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences University, Kanazawa, Japan tamai@p.kanazawa-u.ac.jp.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D015415:Biomarkers / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D027361:Organic Anion Transporters / Q000378:metabolism*; D011237:Predictive Value of Tests; D017208:Rats, Wistar; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D027361:Organic Anion Transporters; D019314:Dehydroepiandrosterone Sulfate; D012293:Rifampin