Cytochrome P450 Inhibitory Properties of Common Efflux Transporter Inhibitors

Englund, Gunilla; Lundquist, Patrik; Skogastierna, Cristine; Johansson, Jenny; Hoogstraate, Janet; Afzelius, Lovisa; Andersson, Tommy; Projean, Denis

doi:10.1124/dmd.113.054932

Cited by 36 publications

(29 citation statements)

References 36 publications

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“…Ketoconazole, itraconazole, and ritonavir have inhibitory actions against other human CYP isoforms in addition to CYP3A . However the values of K i or I C 50 vs .…”

Section: Discussionmentioning

confidence: 99%

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Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

Greenblatt

Harmatz

2015

Brit J Clinical Pharma

119

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AIMSThe regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors. METHODSThe biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (R AUC ) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. RESULTSMean (± SE) R AUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). R AUC values were not significantly related to inhibitor dosage or to duration of inhibitor preexposure prior to administration of MDZ. CONCLUSIONSRitonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well.

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“…Ketoconazole, itraconazole, and ritonavir have inhibitory actions against other human CYP isoforms in addition to CYP3A . However the values of K i or I C 50 vs .…”

Section: Discussionmentioning

confidence: 99%

“…However the values of K i or I C 50 vs . isoforms other than CYP3A are at least one order of magnitude higher (lower inhibitory potency) than for CYP3A . In clinical DDI studies, ketoconazole co‐administration had minimal effects on the pharmacokinetics of antipyrine, caffeine, theophylline, and chlordiazepoxide .…”

Section: Discussionmentioning

confidence: 99%

Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

Greenblatt

Harmatz

2015

Brit J Clinical Pharma

119

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“…For these studies, a tolvaptan concentration of 15 mM and incubation time of 10 minutes were selected. Pioglitazone, verapamil, MK-571, and elacridar at the concentrations tested were selected as inhibitors of canalicular transporters (e.g., P-gp, MRP2, BCRP) (Achira et al, 1999;Englund et al, 2014). These compounds also inhibit CYP3A (IC 50 : 12.3,20,11.3, and 4.9 mM, respectively) (Achira et al, 1999;Sahi et al, 2003;Englund et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…Pioglitazone, verapamil, MK-571, and elacridar at the concentrations tested were selected as inhibitors of canalicular transporters (e.g., P-gp, MRP2, BCRP) (Achira et al, 1999;Englund et al, 2014). These compounds also inhibit CYP3A (IC 50 : 12.3,20,11.3, and 4.9 mM, respectively) (Achira et al, 1999;Sahi et al, 2003;Englund et al, 2014). Tolvaptan accumulation was not markedly altered by 50 mM pioglitazone, verapamil, MK-571, or 10 mM elacridar (data not shown), consistent with the finding that the biliary excretion of tolvaptan was negligible in the present study design.…”

Section: Resultsmentioning

confidence: 99%

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

Slizgi

Brouwer

et al. 2016

Drug Metabolism and Disposition

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Tolvaptan is a selective V 2 -receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatographytandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by tolvaptan and metabolites. Cellular accumulation of tolvaptan (0.15-50 mM), DM-4103, and DM-4107 in SCHH was concentration-dependent.Tolvaptan accumulation (15 mM) in SCHH was not altered markedly by 50 mM pioglitazone, verapamil, MK-571, or 10 mM elacridar. Coincubation of tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing tolvaptan concentrations (0.15-50 mM) decreased TCA (2.5 mM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 mM) had no effect on the cellular accumulation of 2.5 mM pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 mM tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic-and transportermediated DDIs involving tolvaptan and metabolites. IntroductionTolvaptan is an orally available selective V 2 -receptor antagonist used to treat hypervolemic and euvolemic hyponatremia in patients with heart failure and refractory ascites in cirrhosis (Berl et al., 2010;Sakaida, 2014). After oral administration, tolvaptan was absorbed readily from the gastrointestinal tract with an absolute bioavailability of ;50% after a 30-mg dose, and was metabolized extensively, with ;1% of the dose excreted in the urine unchanged (Shoaf et al., 2007(Shoaf et al., , 2012a. CYP3A is the main enzyme involved in tolvaptan metabolism, primarily forming dehydrogenated and hydroxylated metabolites (Shoaf et al., 2012b). DM-4103 and DM-4107 are two major metabolites of tolvaptan primarily excreted in urine and feces, respectively (Tammara et al., 1999). When [ 14 C]tolvaptan was administered orally to rats, biliary excretion was a predominant route of elimination for tolvaptan and metabolites .Hepatocyte cultures preserve whole cellular architecture and function and have been useful for understanding and estimating metabolic clearance and hepatocellular transport (Chiba et al., 2009). In particular, sandwich-cultured human hepatocytes (SCHH) have become a prominent tool to evaluate he...

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“…CsA exhibits a high inter-donor PK variability, directly attributed to the patient's metabolic polymorphism (Fahr, 1993). CsA has been described to be a reversible competitive inhibitor for CYP3A4/5, Pgp (Amundsen et al, 2012;Englund et al, 2014;Fricker and Fahr, 1997;Niwa et al, 2007;Nooter et al, 1990) and other transporters such as the uptake Na + -taurocholate co-transporting polypeptide (NTCP) and efflux bile salt export pump (BSEP), which lead to intra-individual changes in CsA kinetics over time of treatment and its interactions with a variety of drugs in vivo (Bi et al, 2012;Campana et al, 1996;Chiba et al, 2009;De Jonge et al, 2011).…”

Section: Introductionmentioning

confidence: 99%