Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 353; no. 2; pp. 380 - 391
• Main Authors: Shen, Hong, Su, Hong, Liu, Tongtong, Yao, Ming, Mintier, Gabe, Li, Lun, Fancher, R. Marcus, Iyer, Ramaswamy, Marathe, Punit, Lai, Yurong, Rodrigues, A. David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015
• Subjects: Animals; Bile - metabolism; Biological Transport - drug effects; Cyclosporine - pharmacology; Feces - chemistry; Fluorobenzenes - metabolism; Fluorobenzenes - pharmacokinetics; Fluorobenzenes - urine; HEK293 Cells; Humans; Isotope Labeling; Macaca fascicularis; Male; Molecular Probes - metabolism; Molecular Probes - pharmacokinetics; Molecular Probes - urine; Organic Anion Transporters - metabolism; Organic Anion Transporters, Sodium-Dependent - metabolism; Pyrimidines - metabolism; Pyrimidines - pharmacokinetics; Pyrimidines - urine; Rosuvastatin Calcium; Species Specificity; Sulfonamides - metabolism; Sulfonamides - pharmacokinetics; Sulfonamides - urine; Symporters - metabolism; BDC; ATV; ADME; DDI; OATP; RIF; AUC; HEK; CsA; LC-MS/MS; QC; TCA; RSV; NTCP; ESI; HBSS; HPLC; PCR
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.114.221804

Organic anion transporting polypeptides (OATPs) mediate hepatic drug uptake and serve as the loci of drug–drug interactions (DDIs). Consequently, there is a major need to develop animal models and refine in vitro–in vivo extrapolations. Therefore, the in vivo disposition of a model OATP substrate, [3H]rosuvastatin (RSV), was studied in the cynomolgus monkey and reported for the first time. After monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (mean total recovery of radioactivity of 103.6%). Forty-two percent of the RSV dose was recovered in urine and bile, and the elimination pathways were similar to those reported for human subjects; 61.7%, 39.0%, and 2.9% of the dose was recovered in the feces, bile, and urine, respectively. The high levels of unchanged RSV recovered in urine and bile (26% of the dose) and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion. Also, for the first time, the in vitro inhibitory potential of cyclosporin A (CsA) toward cynomolgus monkey OATPs and sodium-taurocholate cotransporting polypeptide was studied in vitro (primary hepatocytes and transporter-transfected cells). It is concluded that one can study the CsA-RSV DDI in the cynomolgus monkey. For example, the in vitro IC50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC0–inf (6.3-fold) and Cmax (10.2-fold) with CsA (100 mg/kg) was similar to that reported for humans. The results further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition.