The multidrug resistance protein Mrp2 is an ATP-binding cassette (ABC) transporter mainly expressed in liver, kidney, and intestine. One of the physiological roles of Mrp2 is to transport bilirubin glucuronides from the liver into the bile. Current in vivo models to study Mrp2 are the transporter-deficient and Eisai hyperbilirubinemic rat strains. Previous reports showed hyperbilirubinemia and induction of Mrp3 in the hepatocyte sinusoidal membrane in the mutant rats. In addition, differences in liver cytochrome P450 and UGT1a levels between wild-type and mutant rats were detected. To study whether these compensatory mechanisms were specific to rats, we characterized Mrp2 Ϫ/Ϫ mice. Functional absence of Mrp2 in the knockout mice was demonstrated by showing increased levels of bilirubin and bilirubin glucuronides in serum and urine, a reduction in biliary excretion of bilirubin glucuronides and total glutathione, and a reduction in the biliary excretion of the Mrp2 substrate dibromosulfophthalein. To identify possible compensatory mechanisms in Mrp2 Ϫ/Ϫ mice, the expression levels of 98 phase I, phase II, and transporter genes were compared in liver, kidney, and intestine of male and female Mrp2 Ϫ/Ϫ and control mice. Unlike in Mrp2 mutant rats, no induction of Mrp3 in Mrp2 Ϫ/Ϫ mice was detected. However, Mrp4 mRNA and protein in liver and kidney were increased ϳ6-and 2-fold, respectively. Phenotypic analysis of major cytochrome P450-mediated activities in liver microsomes did not show differences between wild-type and Mrp2 Ϫ/Ϫ mice. In conclusion, Mrp2Ϫ/Ϫ mice are a new valuable tool to study the role of Mrp2 in drug disposition.
Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8-and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6-and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways.
ABSTRACT:The contribution of human cytochrome P450 (P450) isoforms to the metabolism of aprepitant in humans was investigated using recombinant P450s and inhibition studies. In addition, aprepitant was evaluated as an inhibitor of human P450s. Metabolism of aprepitant by microsomes prepared from baculovirus-expressed human P450s was observed only when CYP1A2, CYP2C19, or CYP3A4 was present in the expression system. Incubation with CYP1A2 and CYP2C19 yielded only products of O-dealkylation, whereas (Navari et al., 1999;Campos et al., 2001). A dosing regimen of aprepitant consists of a combination therapy with a 5-hydroxytryptamine 3 receptor antagonist, such as ondansetron, and a corticosteroid (e.g., dexamethasone, methylprednisolone) (Roila et al., 1998;Gralla et al., 1999). Thus, the use of this novel drug presents a potential for interactions with chemotherapeutic agents as well as adjuvant therapies.In drug-drug interaction studies, it was observed that coadministration with aprepitant resulted in increases in the area under the plasma concentration versus time curve (AUC) for dexamethasone and methylprednisolone . When the standard dexamethasone regimen (20 mg on day 1 and 12 mg on days 2-5) was given concomitantly with aprepitant, dexamethasone AUC 0 -24 h increased ϳ2-fold on both day 1 and day 5 compared with the standard dexamethasone regimen alone. When a modified dexamethasone regimen (12 mg on day 1 and 4 mg on days 2 and 5) was given concomitantly with aprepitant, the dexamethasone AUC 0 -24 h also increased, making it similar to that of the standard regimen alone. When 125 mg of methylprednisolone i.v. on day 1 and 40 mg p.o. on days 2 and 3 was given with aprepitant, the AUC of methylprednisolone increased approximately 30% on day 1 (after i.v. administration) and 2-fold on day 3 (after oral administration). Aprepitant had no effect on either ondansetron (i.v.) or granisetron (p.o.) pharmacokinetics (Blum et al., 2003). Dexamethasone, methylprednisolone, and granisetron are metabolized by CYP3A4 (Glynn et al., 1986;Bloomer et al., 1994;Gentile et al., 1996;Varis et al., 1998), whereas ondansetron is metabolized by multiple P450 isoforms, including CYP1A2, CYP2D6, and CYP3A4 (Fischer et al., 1994;Dixon et al., 1995).Furthermore, clinical drug interaction studies indicated that administration of aprepitant at two different dosing regimens for 5 days altered the pharmacokinetics of the CYP3A4 probe substrate midazolam, when administered on days 1 and 5 of aprepitant therapy. The pharmacokinetic changes included 2.3-and 1.5-fold increases in midazolam AUC and maximum observed plasma concentration, respectively . Collectively, these results suggested that aprepitant is a moderate inhibitor of CYP3A4.
Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ϳ20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (Յ20%) were reported at doravirine concentrations of Ն10 M but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drugmetabolizing enzymes and transporters.
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