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Item Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model(Sage, 2015-12) Patil, Avinash S.; Swamy, Geeta K.; Murtha, Amy P.; Heine, R. Phillips; Zheng, Xiaomei; Grotegut, Chad A.; Department of Obstetrics and Gynecology, IU School of MedicineObjective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility.Item Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts(Wiley, 2019-04-21) Tisdale, James E.; Jaynes, Heather A.; Overholser, Brian R.; Sowinski, Kevin M.; Kovacs, Richard J.; Medicine, School of MedicineIntroduction Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP). Methods and results Female New Zealand white rabbits (2.5–3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n=22) or placebo (n=23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone versus placebo-treated rabbits [3.8 (range, 2.8–5.1) vs 0.7 (0.4–1.7) ng/mL, p<0.0001]. Median serum estradiol concentrations were similar [58 (22–72) versus 53 (34–62) pg/mL), p=0.79]. The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, p=0.049). The incidences of bigeminy (36% vs 74%, p=0.03) and trigeminy (18% vs 57%, p=0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, p=0.54) or monomorphic ventricular tachycardia (14% vs 30%, p=0.28). Maximum QTc interval and short term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits. Conclusions Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy and trigeminy in isolated, perfused AV node-ablated rabbit hearts.