Interactions of Human P-glycoprotein with Simvastatin, Simvastatin Acid, and Atorvastatin

Hochman, Jerome H.; Pudvah, Nicole T.; Qiu, Julia; Yamazaki, Masayo; Tang, Cuyue; Lin, Jiunn H.; Prueksaritanont, Thomayant

doi:10.1023/b:pham.0000041466.84653.8c

Cited by 98 publications

(87 citation statements)

References 23 publications

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“…Furthermore, compounds that are actively transported into the bile in vivo may be pumped back into the medium in these static hepatocyte experiments, which would also artificially increase AUC 0-ϱ . Interestingly, a similar underprediction of CL int ub in vivo using the AUC 0-ϱ method was also observed using human hepatocytes (data not shown) for the known PgP substrate atorvastatin (Hochman et al, 2004) and montelukast. This is particularly pertinent because Zhao et al (2005) have demonstrated an efficient PgP-mediated efflux using human hepatocytes.…”

Section: Contribution Of Hepatic Uptake To Clearancesupporting

confidence: 67%

Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo

Soars¹,

Grime²,

Sproston³

et al. 2007

Drug Metab Dispos

137

128

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ABSTRACT:The wealth of information that has emerged in recent years detailing the substrate specificity of hepatic transporters necessitates an investigation into their potential role in drug elimination. Therefore, an assay in which the loss of parent compound from the incubation medium into hepatocytes ("media loss" assay) was developed to assess the impact of hepatic uptake on unbound drug intrinsic clearance in vivo (CL int ub in vivo ). Studies using conventional hepatocyte incubations for a subset of 36 AstraZeneca new chemical entities (NCEs) resulted in a poor projection of CL int ub in vivo (r 2 ‫؍‬ 0.25, p ‫؍‬ 0.002, average fold error ‫؍‬ 57). This significant underestimation of CL int ub in vivo suggested that metabolism was not the dominant clearance mechanism for the majority of compounds examined. However, CL int ub in vivo was described well for this dataset using an initial compound "disappearance" CL int obtained from media loss assays (r 2 ‫؍‬ 0.72, p ‫؍‬ 6.3 ؋ 10 ؊11 , average fold error ‫؍‬ 3). Subsequent studies, using this method for the same 36 NCEs, suggested that the active uptake into human hepatocytes was generally slower (3-fold on average) than that observed with rat hepatocytes. The accurate prediction of human CL int ub in vivo (within 4-fold) for the marketed drug transporter substrates montelukast, bosentan, atorvastatin, and pravastatin confirmed further the utility of this assay. This work has described a simple method, amenable for use within a drug discovery setting, for predicting the in vivo clearance of drugs with significant hepatic uptake. Prentis et al. (1988) highlighted the importance of drug metabolism and pharmacokinetics (DMPK) in reducing the attrition of candidate drugs in early clinical trials. This has subsequently led to a realignment of DMPK within the drug discovery process and increased use of a plethora of high-throughput screens early in lead optimization (Riley and Grime, 2004).Arguably one of the most critical tasks within DMPK is the accurate prediction of in vivo clearance from in vitro data (Riley, 2001). Although the theory behind this process was published almost 30 years ago (Rane et al., 1977), the potential impact on drug discovery was not fully appreciated until the review by Houston (1994). Subsequently, hepatic microsomes and hepatocytes prepared from both preclinical species and humans have been used to predict in vivo clearance successfully (Obach, 1999;Soars et al., 2002;Ito and Houston, 2004;McGinnity et al., 2004;Ito and Houston, 2005;Riley et al., 2005). However, recent studies with hepatocytes have shown a significant underprediction of in vivo clearance for a distinct set of drugs, which has been attributed in some cases to hepatic uptake Soars et al., 2007).During the last decade a rapid increase has been seen in the number of publications in which researchers have investigated the role of hepatic uptake in drug clearance (Mizuno et al., 2003;Shitara et al., 2006). Perhaps the most important superfamily of enzymes for the hepatic up...

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Section: Contribution Of Hepatic Uptake To Clearancesupporting

confidence: 67%

Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo

Soars¹,

Grime²,

Sproston³

et al. 2007

Drug Metab Dispos

137

128

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“…Indeed, a recent clinical DDI study showed that BOC increased plasma atorvastatin AUC and C max 2.3-and 2.7-fold, respectively (Hulskotte et al, 2011). It is noteworthy that atorvastatin has low intestinal availability [Fa*fg (intestinal availability) = 0.24] (Shitara, 2011) in humans, conceivably due to gut CYP3A4 metabolism and Pgp efflux (Hochman et al, 2004). Therefore, the potential of BOC to inhibit atorvastatin gut metabolism might be an additional contributing factor to the increased systemic exposure of atorvastatin.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldoketoreductases, was a reversible time-dependent inhibitor (k inact = 0.12 minute 21, K I = 6.1 mM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC 50 of 18 and 4.9 mM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.

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“…Recently, it was recognized that a broad variety of drugs, including many cardiovascular drugs such as statins and angiotensin II-receptor antagonists, is transported through biological membranes via specific transport proteins (15,(22)(23)(24). For example, the efflux transporter Pglycoprotein, which translocates its substrates from the inside of the cell to the outside (e.g., from the hepatocyte into bile) is a major determinant of drug effects (1).…”

Section: Discussionmentioning

confidence: 99%

Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

et al. 2008

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OBJECTIVE-The uptake of drugs into hepatocytes is a key determinant for hepatic metabolism, intrahepatic action, their subsequent systemic plasma concentrations, and extrahepatic actions. In vitro and in vivo studies indicate that many drugs used for treatment of cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are taken up into hepatocytes by distinct organic anion transporters (organic anion transporting polypeptides [OATPs]; gene symbol SLCO/SLC21) or organic cation transporters (OCTs; gene symbol SLC22). Because most patients with type 2 diabetes receive more than one drug and inhibition of drug transporters has been recognized as a new mechanism underlying drug-drug interactions, we tested the hypothesis of whether oral antidiabetic drugs can inhibit the transport mediated by hepatic uptake transporters.RESEARCH DESIGN AND METHODS-Using stably transfected cell systems recombinantly expressing the uptake transporters OATP1B1, OATP1B3, OATP2B1, or OCT1, we analyzed whether the antidiabetic drugs repaglinide, rosiglitazone, or metformin influence the transport of substrates and drugs (for OATPs, sulfobromophthalein [BSP] and pravastatin; for OCT1, 1-methyl-4-phenylpyridinium [MPP ϩ ] and metformin).RESULTS-Metformin did not inhibit the uptake of OATP and OCT1 substrates. However, OATP-mediated BSP and pravastatin uptake and OCT1-mediated MPP ϩ and metformin uptake were significantly inhibited by repaglinide (half-maximal inhibitory concentration [IC 50 ] 1.6 -5.6 mol/l) and rosiglitazone (IC 50 5.2-30.4 mol/l).CONCLUSIONS-These in vitro results demonstrate that alterations of uptake transporter function by oral antidiabetic drugs have to be considered as potential mechanisms underlying drug-drug interactions.

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Interactions of Human P-glycoprotein with Simvastatin, Simvastatin Acid, and Atorvastatin

Cited by 98 publications

References 23 publications

Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo

Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

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