title: Metabolite Identification, Reaction Phenotyping, and Retrospective Drug-Drug Interaction Predictions of 17-Deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate.
abstract: Ortho Tri-Cyclen, a two-drug cocktail comprised of ethinylestradiol and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450 (P450), recombinant uridine 5'-diphospho-glucuronosyltransferases, and human liver microsomes in the presence and absence of selective P450 inhibitors were conducted. It was found that CYP3A4 plays a key role in NGMN metabolism with a fraction metabolized (fm) of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4fmvalue, the predicted plasma concentration versus time area under the curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of the reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combinedfmvalue of 1. The data presented in this paper will lead to better understanding and management of NGMN-based drug-drug interactions when norgestimate is coadministered with CYP3A4 modulators.
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center, Syngene International Ltd., Bangalore, India (D.A., S.S., M.S.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersy (B.B., R.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb India Ltd., Bangalore, India: (S.M.).
authors.forename: Deepak
authors.initials: D
authors.lastname: Ahire
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center, Syngene International Ltd., Bangalore, India (D.A., S.S., M.S.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersy (B.B., R.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb India Ltd., Bangalore, India: (S.M.).
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center, Syngene International Ltd., Bangalore, India (D.A., S.S., M.S.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersy (B.B., R.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb India Ltd., Bangalore, India: (S.M.).
authors.forename: Barry
authors.initials: B
authors.lastname: Brock
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center, Syngene International Ltd., Bangalore, India (D.A., S.S., M.S.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersy (B.B., R.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb India Ltd., Bangalore, India: (S.M.).
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Iyer
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center, Syngene International Ltd., Bangalore, India (D.A., S.S., M.S.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersy (B.B., R.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb India Ltd., Bangalore, India: (S.M.).
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center, Syngene International Ltd., Bangalore, India (D.A., S.S., M.S.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersy (B.B., R.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb India Ltd., Bangalore, India: (S.M.) murali.subramanian@syngeneintl.com.
authors.forename: Murali
authors.initials: M
authors.lastname: Subramanian
mesh_terms: D000107:Acetylation; D002853:Chromatography, Liquid; D003280:Contraceptives, Oral, Synthetic / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009644:Norgestrel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: D003280:Contraceptives, Oral, Synthetic; D004338:Drug Combinations; D010091:Oximes; D011994:Recombinant Proteins; D009644:Norgestrel; D003577:Cytochrome P-450 Enzyme System; C017576:norgestimate; C449219:norelgestromin