Identification of the Rate-Determining Process in the Hepatic Clearance of Atorvastatin in a Clinical Cassette Microdosing Study

Abstract

Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose-normalized area under the plasma concentration-time curve (AUC) (4.6-fold), and itraconazole significantly increased the midazolam dose-normalized AUC (1.7-fold). The atorvastatin dose-normalized AUC increased 12-fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that hepatic uptake via OATPs makes the dominant contribution to the hepatic elimination of atorvastatin at a subtherapeutic microdose.

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

“…A single oral dose of 600-mg rifampin greatly increased the AUCs of pitavastatin (Chen et al, 2013, Prueksaritanont et al, 2014, Prueksaritanont et al, 2017, Takehara et al, 2018, rosuvastatin (Prueksaritanont et al, 2014, Prueksaritanont et al, 2017, Wu et al, 2017, Takehara et al, 2018 and atorvastatin (Lau et al, 2007, He et al, 2009, Maeda et al, 2011, Prueksaritanont et al, 2017, Takehara et al, 2018) by 2.8-to 6.7-fold, 3.0-to 4.7-fold, and 4.6-to 12.0-fold, respectively, in multiple clinical DDI studies. In agreement, the administration of 600-mg rifampin in this study resulted in a 2.8-to 3.7-fold elevation in CPI AUC(0-24h) and a 2.…”

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

“…All of these results suggested that the enhanced activity and expression of hepatic Cyp3a were the main contributors to the increases in systemic clearance of simvastatin and simvastatin acid. The uptake of drugs by hepatocytes is also considered a rate-determining process in the hepatic clearance of statins via OATPs [33,34] . The uptake of simvastatin by hepatocytes and the expression of Oatp2 were also investigated.…”

“…Uptake of simvastatin by hepatocytes Uptake of statins by hepatocytes is considered a ratedetermining process in the overall hepatic elimination of statins [33,34] . The uptake of simvastatin by hepatocytes was investigated using freshly isolated rat hepatocytes from experimental rats ( Figure 3D).…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…We further tried to show the rate-limiting step of hepatic clearance of OATP substrates directly in vivo in humans by a cocktail microdosing clinical study. 21) In this study, atorvastatin was selected as a model compound since it is a substrate of both OATPs and CYP3A4. In the first period, a cocktail of microdose (each 33 µg) of atorvastatin, pravastatin (OATP1B1 probe substrate) and midazolam (CYP3A4 probe substrate) was administered to healthy volunteers and the plasma concentrations of these drugs were monitored.…”