Browsing by Author "Hebert, Mary F."

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    Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic
    (Thieme, 2013) Haas, David M.; Quinney, Sara K.; Clay, Jayanti M.; Renbarger, Jamie L.; Hebert, Mary F.; Clark, Shannon; Umans, Jason G.; Caritis, Steve N.; Obstetric-Fetal Pharmacology Research Units Network; Obstetrics and Gynecology, School of Medicine
    Objective: To characterize the pharmacokinetics and pharmacogenetics of nifedipine in pregnancy. Study design: Pregnant women receiving oral nifedipine underwent steady-state pharmacokinetic testing over one dosing interval. DNA was obtained and genotyped for cytochrome P450 (CYP) 3A5 and CYP3A4*1B. Nifedipine and oxidized nifedipine concentrations were measured in plasma, and pharmacokinetic parameters were compared between those women who expressed a CYP3A5*1 allele and those who expressed only variant CYP3A5 alleles (*3,*6, or *7). Results: Fourteen women had complete data to analyze. Four women (29%) expressed variant CYP3A5; three of these women were also CYP3A4*1B allele carriers. The mean half-life of nifedipine was 1.68 ± 1.56 hours. The area under the curve from 0 to 6 hours for the women receiving nifedipine every 6 hours was 207 ± 138 µg·h /L. Oral clearance was different between high expressers and low expressers (232.0 ± 37.8 µg/mL versus 85.6 ± 45.0 µg/mL, respectively; p = 0.007). Conclusion: CYP3A5 genotype influences the oral clearance of nifedipine in pregnant women.
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    Ondansetron Exposure Changes in a Pregnant Woman
    (Wiley, 2016-09) Lemon, Lara S.; Zhang, Hongfei; Hebert, Mary F.; Hankins, Gary D.; Haas, David M.; Caritis, Steve N.; Venkataramanan, Raman; Obstetrics and Gynecology, School of Medicine
    Pregnancy results in many physiologic changes that can alter the pharmacokinetic profiles of medications used during pregnancy. One of the primary factors leading to these pharmacokinetic changes is altered activity of drug-metabolizing enzymes. Ondansetron is a substrate of cytochrome P450 (CYP) 3A4 (primary metabolic pathway), 2D6, and 1A2, all of which are altered during pregnancy. We evaluated the pharmacokinetics of ondansetron at three different gestational time points in a 26-year-old, pregnant, Caucasian woman with normal liver and kidney function, who was maintained on ondansetron 8 mg administered orally 3 times/day throughout her pregnancy. Serial plasma samples were collected from the subject over one 8-hour dosing interval at 14, 24, and 35 weeks’ gestation (representing early-, mid-, and late-pregnancy time points, respectively). Ondansetron plasma concentrations were determined using liquid chromatography-tandem mass spectrometry. Ondansetron area under the plasma concentration–time curve decreased progressively across gestation (634 ng hr/ml in early pregnancy, 553 ng hr/ml in mid-pregnancy, and 387 ng hr/ml in late pregnancy), with a corresponding increase in apparent oral clearance (12.6 L/hr in early-pregnancy, 14.5 L/hr in midpregnancy, and 20.7 L/hr in late-pregnancy). The decreased area under the plasma concentration–time curve and exposure to ondansetron across gestation is likely due to increased activity of CYP3A4 and CYP2D6 during pregnancy. We were not able to study this patient during the postpartum period; however, as with other CYP3A4 and CYP2D6 substrates, the apparent activities of these isoenzymes are likely return to baseline. To our knowledge, this is the first report to describe ondansetron pharmacokinetics across gestation. Additional pharmacokinetic and pharmacodynamic data are needed to confirm our results and to evaluate clinical impact; however, in the meantime, clinicians should be aware of these pharmacokinetic changes in ondansetron exposure during pregnancy.