RT Journal Article
SR Electronic
T1 Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 380
OP 391
DO 10.1124/jpet.114.221804
VO 353
IS 2
A1 Hong Shen
A1 Hong Su
A1 Tongtong Liu
A1 Ming Yao
A1 Gabe Mintier
A1 Lun Li
A1 R. Marcus Fancher
A1 Ramaswamy Iyer
A1 Punit Marathe
A1 Yurong Lai
A1 A. David Rodrigues
YR 2015
UL http://jpet.aspetjournals.org/content/353/2/380.abstract
AB 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.