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, [ 3 H]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 IC 50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC 0-inf (6.3-fold) and C max (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.
Identification
of a selective inhibitor of organic anion transporting polypeptide
(OATP) 1B1 is critical in order to determine the contribution of OATP1B1-mediated
uptake of investigational drugs into human hepatocytes for successful
in vitro-to-in vivo extrapolation (IVIVE) of hepatic uptake and drug–drug
interaction (DDI). The following study examined the inhibitory effects
of estropipate (EPP) on major sinusoidal drug uptake transporters
and explored its utility regarding IVIVE of statin hepatic disposition.
EPP and its free-base form (i.e., estrone sulfate) showed a potent
and high degree of selectivity in inhibiting the OATP1B1-mediated
transport of rosuvastatin with an IC50 value averaging
0.05 ± 0.01 and 0.12 ± 0.07 μM for human and cynomolgus
monkey OATP1B1 (hOATP1B1 and cOATP1B1), respectively, whereas weak
inhibition was observed for human and monkey OATP1B3, OATP2B1, sodium-taurocholate
cotransporting polypeptide (NTCP), organic anion transporter 2, and
organic cation transporter 1 with IC50 values ranging from
8.6 to 64.0 μM. EPP, together with rifamycin SV, was subsequently
used to determine the fractions of hepatic uptake clearance (f
T) of statins, including rosuvastatin, pitavastatin,
and dehydropravastatin, which are reported to be mediated by OATP1B1,
OATP1B3, OATP2B1, and NTCP. Finally, the magnitudes of in vivo inhibition
of rosuvastatin clearance caused by EPP and rifampin in cynomolgus
monkeys were predicted by using individual transporter IC50 and f
T (AUC fold change 1.28 vs 1.21,
2.71 vs 1.75, and 3.35 vs 2.83, respectively). These results suggest
that EPP is an appropriate OATP1B1-selective inhibitor to establish
the relative contribution of OATP1B1 to hepatic uptake in vitro and
to discern the role of OATP1B1 in hepatic disposition in vivo.
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