Dataset Information

An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes.

ABSTRACT: Relacorilant is a selective modulator of the glucocorticoid receptor in development for the treatment of several serious diseases. The widely used cocktail method was employed to assess relacorilant's effect on various cytochrome P450 (CYP) drug metabolizing enzymes in vitro and in vivo. Inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 as well as induction of CYP1A2, CYP2B6, and CYP3A4 were assessed in vitro (relacorilant concentrations up to 10 µM). A clinical study in healthy subjects (n = 27) evaluated the inhibition of CYP3A4, CYP2C8, and CYP2C9 in vivo by administering single doses of probe CYP substrates (midazolam, pioglitazone, and tolbutamide) alone and in combination with relacorilant (350 mg). Pharmacokinetic sampling was conducted, and safety was assessed throughout the study. Pharmacokinetic parameters were evaluated using 90% confidence intervals of the geometric least squares mean ratios of test (probe substrate with relacorilant) vs reference (probe substrate alone) using boundaries of 80% to 125%. In vitro, relacorilant inhibited CYP3A4, CYP2C8, and CYP2C9 but did not meaningfully affect the activity of the other CYP enzymes evaluated. Consistent with the in vitro data, relacorilant was shown to be a strong CYP3A inhibitor in vivo (>8-fold increase in midazolam area under the concentration versus time curve from time zero to the last quantifiable concentration and area under the concentration versus time curve from time zero extrapolated to infinity). Coadministration of relacorilant with drugs highly dependent on CYP3A for clearance is expected to increase the concentrations of these drugs. Importantly, clinical evaluation of relacorilant showed no inhibition of CYP2C8 or CYP2C9 in vivo. Accordingly, drugs that are substrates of only CYP2C8 and/or CYP2C9 can be coadministered with relacorilant without dose adjustment.

SUBMITTER: Custodio JM

PROVIDER: S-EPMC7818505 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes.

Custodio Joseph M JM Donaldson Kirsteen M KM Hunt Hazel J HJ

Journal of clinical pharmacology 20200831 2

Relacorilant is a selective modulator of the glucocorticoid receptor in development for the treatment of several serious diseases. The widely used cocktail method was employed to assess relacorilant's effect on various cytochrome P450 (CYP) drug metabolizing enzymes in vitro and in vivo. Inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 as well as induction of CYP1A2, CYP2B6, and CYP3A4 were assessed in vitro (relacorilant concentrations up to 10 µM). A clinical s ...[more]

PMID: 32869328

Similar Datasets

Project description:AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug-drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5'-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4'-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4'-hydroxylation, and CYP2D6-catalyzed bufuralol 1'-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug-drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

Dataset Information

An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes.

Publications

An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets