Prediction of the in vivo OATP1B1-mediated drug–drug interaction potential of an investigational drug against a range of statins

Sharma, Pradeep; Butters, Caroline; Smith, Veronica; Elsby, Robert; Surry, Dominic

doi:10.1016/j.ejps.2012.04.003

Cited by 48 publications

(48 citation statements)

References 39 publications

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“…The interaction profiles of SMV, ASV, DCV, and SFV with OATP1B1 and OATP1B3 were examined by a classical coincubation inhibition assay, where TLV was also used as a reference DAA. E 2 G and CCK-8 were used as OATP1B1 and OATP1B3 substrates, respectively, because they have come to be regarded as good surrogate probes for evaluation of OATP1B-mediated DDIs (9,23). The results showed that all DAAs tested were able to inhibit OATP1B1 function (Fig.…”

Section: Resultsmentioning

confidence: 84%

“…This range could be further expanded as the patient population increases, partially because of the presence of rare variants in the drug-metabolizing and transporter genes (26,27). Second, although E 2 G and CCK-8 have been considered good surrogate probes for use in OATP1B inhibition studies (9,23), the R value obtained from other OATP1B substrates may be different from the values obtained in this study, as exemplified by the report showing that the IC 50 values of rifamycin SV toward OATP1B1-mediated E 2 G and rosuvastatin uptake are 0.34 Ϯ 0.05 and 0.05 Ϯ 0.02 (M), respectively (23). Finally, because various enzymes and transporters, such as CYP3A4, cooperatively determine a drug pharmacokinetic profile together with OATP1Bs, multifactor evaluation of clinical DDI likelihood is necessary in order to minimize over-or underprediction, as depicted in the recent literature (28).…”

Section: Discussionmentioning

confidence: 99%

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Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Furihata

Matsumoto

et al. 2014

Antimicrob Agents Chemother

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b Simeprevir (SMV), asunaprevir (ASV), daclatasvir (DCV), and sofosbuvir (SFV), which are newly developed direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection, are among the key components of anti-HCV regimens. Preclinical studies have identified inhibitory properties for some of these DAAs against organic anion transporting polypeptide 1B (OATP1B) functions. However, their details remain mostly uncharacterized. Because OATP1B1 and OATP1B3 play determinant roles in the pharmacokinetics of various drugs via their uptake into human hepatocytes, it is plausible that the inhibition of these OATP1Bs by a DAA would create a potential risk of drug-drug interaction, which has been an emerging concern in anti-HCV therapy. Accordingly, in the present study, we intended to clarify the inhibitory characteristics of newly developed DAAs toward OATP1B1 and -1B3 functions. The results of our coincubation inhibition assays have shown that all tested DAAs could inhibit OATP1B1 functions and that SMV, ASV, and DCV (to a lesser extent), but not SFV, exhibited long-lasting preincubation inhibitory effects on OATP1B1 functions. It was also found that the preincubation inhibitory effects of SMV and ASV could augment their coincubation inhibition potency. Furthermore, significant, but differential, inhibitory effects of the DAAs on the OATP1B3 function were identified. To summarize, our results clearly show that the newly developed DAAs are newly identified OATP1B1 and OATP1B3 inhibitors with distinctive interaction properties. It is believed that these inhibition profiles will provide essential information to all concerned parties with respect to the clinical significance of DAA-mediated inhibition of OATP1Bs in anti-HCV therapy.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Furihata

Matsumoto

et al. 2014

Antimicrob Agents Chemother

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“…We anticipated the I in,max,u value to be 12 mg/ml (24 mM) for FA in rats. A low victim drug dose, 3 mg/kg rosuvastatin, was selected such that I in,max,u would be less than its OATP1B1 K M or 9 mM (Sharma et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy

Eng

Scialis

Rotter

et al. 2016

Drug Metabolism and Disposition

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Chronic treatment of methicillin-resistant Staphylococcus aureus strains with the bacteriostatic agent fusidic acid (FA) is frequently associated with myopathy including rhabdomyolysis upon coadministration with statins. Because adverse effects with statins are usually the result of drug-drug interactions, we evaluated the inhibitory effects of FA against human CYP3A4 and clinically relevant drug transporters such as organic anion transporting polypeptides OATP1B1 and OATP1B3, multidrug resistant protein 1, and breast cancer resistance protein, which are involved in the oral absorption and/or systemic clearance of statins including atorvastatin, rosuvastatin, and simvastatin. FA was a weak reversible (IC 50 = 295 6 1.0 mM) and time-dependent (K I = 216 6 41 mM and k inact = 0.0179 6 0.001 min 21) inhibitor of CYP3A4-catalyzed midazolam-19-hydroxylase activity in human liver microsomes. FA demonstrated inhibition of multidrug resistant protein 1-mediated digoxin transport with an IC 50 value of 157 6 1.0 mM and was devoid of breast cancer resistance protein inhibition (IC 50 > 500 mM). In contrast, FA showed potent inhibition of OATP1B1-and OATP1B3-specific rosuvastatin transport with IC 50 values of 1.59 mM and 2.47 mM, respectively. Furthermore, coadministration of oral rosuvastatin and FA to rats led to an approximately 19.3-fold and 24.6-fold increase in the rosuvastatin maximum plasma concentration and area under the plasma concentration-time curve, respectively, which could be potentially mediated through inhibitory effects of FA on rat Oatp1a4 (IC 50 = 2.26 mM) and Oatp1b2 (IC 50 = 4.38 mM) transporters, which are responsible for rosuvastatin uptake in rat liver. The potent inhibition of human OATP1B1/OATP1B3 by FA could attenuate hepatic uptake of statins, resulting in increased blood and tissue concentrations, potentially manifesting in musculoskeletal toxicity.

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“…Currently, various clinically used drugs including statins (Sharma et al, 2012), angiotensin II receptor blockers (Yamashiro et al, 2006), endothelin receptor antagonists , antidiabetics (Takanohashi et al, 2012), and diuretics (Werner et al, 2010) are known as OATP1B1 substrates. These clinically used OATP1B1 substrate drugs, in addition to prototypical substrates, could also serve as in vitro probe substrates because of their clinical relevance.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

Izumi¹,

Nozaki²,

Maeda³

et al. 2014

Drug Metab Dispos

132

139

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The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17b-glucuronide (E 2 G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The K i values (mM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the K i values were within 2.8-fold of those obtained using E 2 G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the K i values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E 2 G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substratedependent K i variation.

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Prediction of the in vivo OATP1B1-mediated drug–drug interaction potential of an investigational drug against a range of statins

Cited by 48 publications

References 39 publications

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

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