title: Effect of dimethyl sulfoxide on in vitro cytochrome P4501A2 mediated phenacetin O-deethylation in human liver microsomes.
abstract: In this study, we report the effect of dimethyl sulfoxide (DMSO), acetonitrile, and methanol on the CYP1A2-mediated metabolism of phenacetin in human liver microsomes. Phenacetin O-deethylation is the preferred probe reaction for CYP1A2, in which the metabolite, acetaminophen, is quantified using liquid chromatography-tandem mass spectrometry. DMSO was found to inhibit CYP1A2-mediated phenacetin O-deethylation even at low concentrations (0.1%). Acetonitrile did not significantly change the phenacetin O-deethylation activity at concentrations up to 2%. There was no effect on the phenacetin O-deethylation when methanol was present at levels up to 2%. We found that the DMSO level should be kept lower than 0.05% because a concentration of 0.1% strongly affected the metabolism of phenacetin. These findings should be taken into consideration when designing in vitro metabolism studies, especially studies in which metabolism of the investigational compound needs to be evaluated, which would confound the results. The findings from this study indicate that methanol is the suitable solvent and has no significant effects on CYP1A2-mediated phenacetin O-deethylation.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue 7, Banjara Hills, Hyderabad 500 034, India. Ramakrishna_nirogi@yahoo.co.in
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Nirogi
authors.forename: Vishwottam
authors.initials: V
authors.lastname: Kandikere
authors.forename: Gopinadh
authors.initials: G
authors.lastname: Bhyrapuneni
authors.forename: Ranjith Kumar
authors.initials: RK
authors.lastname: Ponnamaneni
authors.forename: Raghava choudary
authors.initials: Rc
authors.lastname: Palacharla
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Manoharan
mesh_terms: D000082:Acetaminophen / Q000378:metabolism; D000097:Acetonitriles / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D006801:Humans; D000432:Methanol / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D010615:Phenacetin / Q000378:metabolism*; D012997:Solvents
chemical_list: D000097:Acetonitriles; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D012997:Solvents; D000082:Acetaminophen; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D010615:Phenacetin; D000432:Methanol; D004121:Dimethyl Sulfoxide; C032159:acetonitrile