Drug metabolism and transport during pregnancy: how does drug disposition change during pregnancy and what are the mechanisms that cause such changes?

Drug Metab Dispos. 2013 Feb;41(2):256-62. doi: 10.1124/dmd.112.050245.

Abstract

There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestational-stage and tissue-specific manner. In vivo probe studies have shown that the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. The activity of some renal transporters, including organic cation transporter and P-glycoprotein, also appears to be increased during pregnancy. Although much has been learned, significant gaps still exist in our understanding of the spectrum of drug metabolism and transport genes affected, gestational age-dependent changes in the activity of encoded drug metabolizing and transporting processes, and the mechanisms of pregnancy-induced alterations. In this issue of Drug Metabolism and Disposition, a series of articles is presented that address the predictability, mechanisms, and magnitude of changes in drug metabolism and transport processes during pregnancy. The articles highlight state-of-the-art approaches to studying mechanisms of changes in drug disposition during pregnancy, and illustrate the use and integration of data from in vitro models, animal studies, and human clinical studies. The findings presented show the complex inter-relationships between multiple regulators of drug metabolism and transport genes, such as estrogens, progesterone, and growth hormone, and their effects on enzyme and transporter expression in different tissues. The studies provide the impetus for a mechanism- and evidence-based approach to optimally managing drug therapies during pregnancy and improving treatment outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Comment

MeSH terms

  • 17 alpha-Hydroxyprogesterone Caproate
  • ATP-Binding Cassette Transporters / metabolism*
  • Adrenal Glands / enzymology*
  • Animals
  • Aryldialkylphosphatase / metabolism*
  • Carboxylesterase / metabolism*
  • Cholestasis / metabolism*
  • Cotinine / metabolism*
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / agonists*
  • Estrogens / pharmacology*
  • Ethinyl Estradiol / pharmacology*
  • Female
  • Fetus / drug effects*
  • Gene Expression Regulation, Developmental / drug effects*
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism*
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism*
  • Humans
  • Hydroxyprogesterones / metabolism*
  • Intestine, Small / enzymology*
  • Kidney / enzymology*
  • Kidney / metabolism*
  • Liver / drug effects*
  • Liver / enzymology*
  • Lung / enzymology*
  • Male
  • Maternal Behavior*
  • Membrane Transport Proteins / metabolism*
  • Minor Histocompatibility Antigens
  • Multidrug Resistance-Associated Proteins / drug effects*
  • Organic Anion Transporters / metabolism*
  • Pesticides / metabolism*
  • Placenta / drug effects*
  • Placenta / enzymology*
  • Pregnancy
  • Progesterone / pharmacology*
  • RNA, Messenger / biosynthesis*
  • Retinoic Acid 4-Hydroxylase
  • Smoking / adverse effects*
  • Taurocholic Acid / metabolism*

Substances

  • ATP-Binding Cassette Transporters
  • Estrogen Receptor alpha
  • Estrogens
  • Hydroxyprogesterones
  • Membrane Transport Proteins
  • Minor Histocompatibility Antigens
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • Pesticides
  • RNA, Messenger
  • multidrug resistance-associated protein 3
  • 17 alpha-Hydroxyprogesterone Caproate
  • Ethinyl Estradiol
  • Progesterone
  • Estradiol
  • Taurocholic Acid
  • Cytochrome P-450 Enzyme System
  • Retinoic Acid 4-Hydroxylase
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • UDP-glucuronosyltransferase 2B15, human
  • UGT2B17 protein, human
  • Carboxylesterase
  • Aryldialkylphosphatase
  • PON1 protein, mouse
  • Cotinine