title: Evaluation of the impact of 16-dehydropregnenolone on the activity and expression of rat hepatic cytochrome P450 enzymes.
abstract: 16-dehydropregnenolone (DHP) is a promising novel antihyperlipidemic agent developed and patented by Central Drug Research Institute (CDRI), India. The purpose of the present study was to investigate whether DHP influences the activities and mRNA expression of hepatic drug-metabolizing cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D2, CYP2E1 and CYP3A1) in Sprague-Dawley (SD) rats. A cocktail suspension of CYP probe substrates which contained caffeine (CYP1A2), tolbutamide (CYP2C11), dextromethorphan (CYP2D2), chlorzoxazone (CYP2E1) and dapsone (CYP3A1) was administered orally on eighth- or fifteenth-day to rats pre-treated with DHP intragastrically at a dose of 36 and 72mg/kg for one week and two weeks. The concentrations of probe drugs in plasma were estimated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Alongside, the effect of DHP on CYPs activity and mRNA expression levels were assayed in isolated rat liver microsomes and by real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively. DHP had significant inducing effects on CYP1A2, 2C11, 2D2 and 2E1 with no effect on CYP3A1 in dose- and time-dependent manner, as revealed from the pharmacokinetic profiles of the probe drugs in rats. In-vitro microsomal activities and mRNA expression results were in good agreement with the in-vivo pharmacokinetic results. Collectively, the results unveiled that DHP is an inducer of rat hepatic CYP enzymes. Hence, intense attention should be paid when DHP is co-administered with drugs metabolized by CYP1A2, 2C11, 2D2 and 2E1, which might result in drug-drug interactions and therapeutic failure.
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi, 110001, India.
authors.forename: Rachumallu
authors.initials: R
authors.lastname: Ramakrishna
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi, 110001, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Bhateria
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Rajbir
authors.initials: R
authors.lastname: Singh
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi, 110001, India. Electronic address: rabi_bhatta@cdri.res.in.
authors.forename: Rabi Sankar
authors.initials: RS
authors.lastname: Bhatta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D002753:Chlorzoxazone / Q000378:metabolism / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2 / Q000235:genetics* / Q000378:metabolism; D003622:Dapsone / Q000378:metabolism / Q000494:pharmacology; D003915:Dextromethorphan / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011284:Pregnenolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D014044:Tolbutamide / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000960:Hypolipidemic Agents; D002110:Caffeine; C003592:16-dehydropregnenolone; D003915:Dextromethorphan; D011284:Pregnenolone; D003622:Dapsone; D014044:Tolbutamide; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C017170:Cyp1a2 protein, rat; C119985:Cyp2d2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D002753:Chlorzoxazone
keywords: 16-dehydropregnenolone; CYP450; Cocktail; Microsomes; Pharmacokinetics; Real time RT-PCR