title: Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction.
abstract: The objective of the study was to evaluate the metabolism dependent inhibition of CYP2B6 catalyzed bupropion hydroxylation in human liver microsomes by monoamine oxidase (MAO) inhibitors and to predict the drug-drug interaction potential of monoamine oxidase inhibitors as perpetrators of drug interaction. Human liver microsomal CYP2B6 activities were investigated using bupropion hydroxylation as probe substrate marker. The results from single point time dependent inhibition and shift assays suggest that clorgyline, pargyline, phenelzine, and selegiline were metabolism based inhibitors of CYP2B6. In IC50 shift assays, clorgyline, pargyline, phenelzine and selegiline are metabolism based inhibitors of CYP2B6 with fold shit of 3.0-, 3.7-, 2.9-, and 11.4-fold respectively. The inactivation of clorgyline was characterized by KI value of 2.5 ± 0.3 and k(inact) value of 0.045 ± 0.001 min(-1). Phenelzine inactivated CYP2B6 with KI and k(inact) values of 44.9 ± 6.9 μM and 0.085 ± 0.003 min(-1) respectively. Inactivation of selegiline was characterized with KI and k(inact) values of 22.0 ± 3.3 and 0.074 ± 0.002 min(-1) respectively. The inactivation caused by these inhibitors was not reversed by dialysis indicating irreversible inhibition. Based on the mechanistic static model, selegiline showed an increase in the area under the curve (AUC) of efavirenz and bupropion by 1.01-fold. Phenelzine predicted to cause an increase in the AUC of efavirenz and bupropion by 9.4- and 2.4-fold respectively considering unbound hepatic inlet concentrations of phenelzine. In conclusion, the results from this study demonstrated that MAO inhibitors can inactivate human liver microsomal CYP2B6. The likelihood of drug interaction when selegiline co-administered with CYP2B6 substrates is remote. Caution is required while co-administering phenelzine with substrates that are exclusively metabolized by CYP2B6 enzyme and substrates that have narrow therapeutic index.
authors: Discovery Research, Suven Life Sciences Limited, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India. Electronic address: nvsrk@suven.com.
authors: Ramakrishna
authors: R
authors: Nirogi
authors: Department of Drug Metabolism and Pharmacokinetics, Suven Life Sciences Ltd, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India.
authors: Raghava Choudary
authors: RC
authors: Palacharla
authors: Department of Medicinal Chemistry, Suven Life Sciences Limited, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India.
authors: Abdul Rasheed
authors: AR
authors: Mohammed
authors: Department of Drug Metabolism and Pharmacokinetics, Suven Life Sciences Ltd, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India.
authors: Arunkumar
authors: A
authors: Manoharan
authors: Department of Drug Metabolism and Pharmacokinetics, Suven Life Sciences Ltd, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India.
authors: Ranjith Kumar
authors: RK
authors: Ponnamaneni
authors: Department of Drug Metabolism and Pharmacokinetics, Suven Life Sciences Ltd, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India.
authors: Gopinadh
authors: G
authors: Bhyrapuneni
mesh_terms: D016642:Bupropion / Q000378:metabolism / Q000493:pharmacokinetics*; D003010:Clorgyline / Q000494:pharmacology; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism*; D065686:Cytochrome P-450 CYP2B6 Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D007697:Kinesics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D010624:Phenelzine / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology
chemical_list: D065686:Cytochrome P-450 CYP2B6 Inhibitors; D008996:Monoamine Oxidase Inhibitors; D016642:Bupropion; D012642:Selegiline; D010293:Pargyline; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D005978:Glutathione; D003010:Clorgyline; D010624:Phenelzine
keywords: CYP2B6; Drug interaction; Metabolism based inhibition; Selegiline; Static model