The objectives of the study were to evaluate the effects of pregnancy on CYP3A and P-glycoprotein (P-gp) activities, as measured by disposition of midazolam and digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) and midazolam (2 mg p.o.) in random order, separated by 1-2 weeks at 28-32 weeks gestation, and the same order was repeated at 6-10 weeks postpartum. Plasma and urine concentrations were determined by liquid chromatography-mass spectrometry and analyzed by noncompartmental methods. Midazolam CL/F(unbound) (593 +/- 237 l/min vs. 345 +/- 103 l/min; P = 0.007), digoxin CL(Renal, unbound) (272 +/- 45 ml/min vs. 183 +/- 37 ml/min; P < 0.002) and digoxin CL(secretion,) (unbound) (109 +/- 34 ml/min vs. 58 +/- 22 ml/min; P < 0.002) were higher during pregnancy than postpartum. These data are consistent with increased hepatic and/or intestinal CYP3A and renal P-gp activities during pregnancy.

Glyburide's PK and PD have not been studied in women with gestational diabetes mellitus (GDM). The objective was to assess steady-state PK of glyburide as well as insulin sensitivity, beta-cell responsivity and overall disposition indices following a mixed meal tolerance test (MMTT) in GDM (n=40), non-pregnant type 2 diabetic (T2DM) (n=26) and healthy pregnant (n=40, MMTT only) women. At equivalent doses, glyburide plasma concentrations were ~50% lower in pregnancy compared to non-pregnant women. Average glyburide umbilical cord to maternal plasma concentration ratio at the time of delivery was 0.7 ± 0.4. Insulin sensitivity was ~5-fold lower in women with GDM compared to healthy pregnancy. Despite comparable beta-cell responsivity index, average beta-cell function corrected for insulin resistance was >3.5-fold lower in women with glyburide-treated GDM than healthy pregnancy. Women with GDM that fail glyburide may benefit from alternate medication selection or dosage escalation, though fetal safety should be considered.Corresponding Author and Reprint Requests: Mary F. Hebert, Pharm.D., FCCP, University of Washington, Department of Pharmacy, 1959 NE Pacific St., H-375 Health Science Center, Box 357630, Seattle WA 98195-7630, Phone: 206-616-5016, Fax: 206-543-3835, Email: E-mail: mhebert@u.washington.edu. * Current address: Pfizer Global Research and Development, San Diego CA CONFLICT OF INTEREST/DISCLOSURE At the time of study conduct and analysis, the authors declare no conflict of interest. However, since completion of the study, Dr. Vicini's affiliation has become Pfizer Global Research and Development. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2010 June 1. Published in final edited form as:Clin Pharmacol Ther. Gestational diabetes mellitus (GDM) complicates 5-12% of pregnancies and is associated with adverse pregnancy outcomes. Insulin has been the mainstay of pharmacotherapy for GDM. Glyburide's (GLY) advantages include easier route of administration and schedule as well as improved patient satisfaction and adherence. GLY's acceptance has been due to its comparable efficacy with insulin and limited transfer to the fetus.(1,2) However, the pharmacokinetics (PK) of GLY have not been studied in pregnancy and dosage strategies generally follow those used in non-pregnant patients with type 2 diabetes mellitus (T2DM). We hypothesized that the PK of GLY would be different during pregnancy, due to the expected changes in metabolism, protein binding, and body composition. In addition, the effects of GLY on the insulin sensitivity and secretion parameters have not been systematically studied. Our objectives were to compare GLY PK in women with GDM and non-pregnant T2DM, to measure fetal exposure to glyburide at delivery and to evaluate insulin sensitivity (SI), beta-cell responsivity index (Φ total ) and disposition index (DI) following a mixed meal tolerance test (MMTT) in women with GDM on GLY therapy, compared with gestational age-matched healthy pregnant ...

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We conducted a randomized, double-blind trial to compare analgesia and side effects produced by ketorolac and morphine during postoperative patient-controlled analgesia (PCA). Fifty-one patients (ASA classes I and II) undergoing elective intraabdominal procedures were assigned to one of two groups. When postoperative pain first increased to 4/10 (by visual analog scale [VAS]), patients were randomly assigned to one of two groups. Group 1 (n = 25) received up to two intravenous (IV) boluses of 5 mg of morphine followed by IV morphine PCA, whereas those in Group 2 (n = 26) received up to two IV boluses of 30 mg ketorolac, then IV ketorolac PCA. Up to two rescue doses of morphine (5 mg per dose, subcutaneously) were given in either group when pain during deep inhalation exceeded 5/10 on VAS. Ten patients from Group 1 required rescue doses of morphine compared to 22 patients from Group 2 (P < 0.0011). Two and 16 patients from Groups 1 and 2, respectively, were withdrawn because of inadequate analgesia (P < 0.01). Mean pain scores were less in Group 1 than in Group 2 at each time, but only significantly so at 15 min (P < 0.0021), 30 min (P < 0.0336), and 24 h (P < 0.0358) after starting PCA. Time to acceptance of oral liquids was equivalent in Groups 1 and 2 (22 h and 21 h, respectively). IV ketorolac PCA, although well tolerated, has limited effectiveness as the sole postoperative analgesic after intraabdominal operations.

Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation.

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Dose-response curves of three receptor-selective opioids were established in a group of nonburned and a group of burned rats. Morphine (mu-agonist), biphalin (mu- and delta-agonist), and U50488H (kappa-agonist) were administered to each group, and analgesia was measured by tail flick latency testing. Each opioid had a significant increase in potency (i.e., a decrease in ED50 values) in the burned (15% body surface area) compared with the nonburned groups. Moderate doses of each drug (i.e., ED50 doses estimated from nonburned group data) in each case augmented stress-induced analgesia in the burned group. Analgesic doses failed to prevent a significant increase in plasma beta-endorphin and corticosterone after larger surface area (25%) burns. Regardless of receptor specificity, opioid analgesic potency is increased acutely after burn injuries.