title: Consequences of daily corticosteroid dosing with or without pre-treatment with quinidine on the in vivo cytochrome P450 2D (CYP2D) enzyme in rats: effect on O-demethylation activity of dextromethorphan and expression levels of CYP2D1 mRNA.
abstract: 1. Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate. 2. CYP2D1 mRNA was measured in liver homogenate using quantitative real-time polymerase chain reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10 mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10 mg/kg corticosteroids for five days. 3. Five days repeat dosing of dexamethasone or prednisolone decreased the activity of the rat liver CYP2D by 37% and 34%, at 30 min incubation and decreased CYP2D1 mRNA levels by 62% and 61%, respectively. 4. Pre-treatment of quinidine decreased the enzymatic activity of rat CYP2D by 58% and did not potentiate CYP2D inhibition by corticosteroids. This observation was further complemented by qRT-PCR data. 5. Corticosteroids caused CYP2D inhibition in rats vs. literature evidence of CYP2D induction in human hepatocytes/pregnant humans demonstrating lack of concordance. In vivo inhibition should be factored for interpretation of pharmacokinetic data of CYP2D substrates when treated with corticosteroids in rats.
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Poonam
authors.initials: P
authors.lastname: Giri
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Prashant
authors.initials: P
authors.lastname: Delvadia
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Laxmikant
authors.initials: L
authors.lastname: Gupta
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Patel
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Priyal
authors.initials: P
authors.lastname: Trivedi
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Krishna
authors.initials: K
authors.lastname: Lad
authors.affiliation: b Department of Molecular Pharmacology , Zydus Research Centre , Ahmedabad , India.
authors.forename: Hiren M
authors.initials: HM
authors.lastname: Patel
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , Zydus Research Centre , Ahmedabad , India and.
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D000072467:Cytochrome P450 Family 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000073398:Demethylation; D003915:Dextromethorphan / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats
chemical_list: D000305:Adrenal Cortex Hormones; D004791:Enzyme Inhibitors; D003915:Dextromethorphan; C504568:Cyp2d1 protein, rat; D000072467:Cytochrome P450 Family 2; D011802:Quinidine
keywords: CYP2D; corticosteroids; dexamethasone; humans; pharmacokinetics; prednisolone