A broad pharmocipia of drugs are used in pregnancy. Despite this, our knowledge of the disposition of drug to the fetus and how the fetus metabolizes various drugs is limited. Glucuronyltransferase, a common phase II conjugation system, is down regulated in the fetus and undergoes induction near birth. Despite the limited activity of this enzyme in utero, we have shown that fetal glucuronidation of drugs can have significant effects on fetal concentration of both drugs and their metabolites in the fetus. Drug concentrations are diminished and metabolite concentrations can exceed those in the mother. Furthermore. premature induction of these enzymes could lead to more pronounced effects. To predict the likely effect a drug will have on the fetus, pharmacokinetic models are required to estimate fetal drug and metabolite concentrations. Using glucuronyltransferase as a model, the goal of this proposal, is to establish the role of fetal metabolism in overall maternal-fetal pharmacokinetics. Our overall hypothesis is that fetal metabolism accounts for a significant amount of the observed nonplacental clearance of drug from the fetus. In addition, measures of glucuronyltransferase expression during fetal life will predict the observable changes in fetal drug and metabolite concentrations. We propose to test these hypotheses by a series of experiments in the fetal baboon. A novel pharmacokinetic approach to the quantification of the rate of formation of glucuronide metabolites in the fetal baboon will be combined with biochemical assays of glucuronyltransferase activity and quantitative measures of expressed protein (protein immunoanalysis and steady-state mRNA) in fetal tissues. We will quantify the rate of glucuronide formation of buprenorphine, imipramine, acetominophen, and morphine in the fetal baboon across late gestation and correlate this with biochemical measures of enzyme-activity. We will quantify the change in metabolism following exposure to phenobarbital and dexamethasone, known inducers of glucuronyltransferase, and then quantify the effect this has on steady-state fetal-to-maternal ratios following maternal drug administration. In conjunction with recent advances in pharmacologic therapy for pregnant women, there is a pressing need for developing pharmacokinetic models which reliably define drug levels in the fetus. The long-term goal of this research is to reverse a trend which left the fetus as a therapeutic orphan.
| Abildskov, Kirsten; Weldy, Piper; Garland, Marianne (2010) Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos 38:545-53 |
| Garland, Marianne; Abildskov, Kirsten M; Kiu, Tung-Wah et al. (2008) Placental transfer and fetal elimination of morphine-3-beta-glucuronide in the pregnant baboon. Drug Metab Dispos 36:1859-68 |
| Caspersen, Casper S; Reznik, Boris; Weldy, Piper L et al. (2007) Molecular cloning of the baboon UDP-glucuronosyltransferase 1A gene family: evolution of the primate UGT1 locus and relevance for models of human drug metabolism. Pharmacogenet Genomics 17:11-24 |
