Maternal-fetal pharmacokinetics of methanol.
We undertook the present project to elucidate the physiologic factors that govern methanol delivery to the developing conceptus after maternal methanol exposure, and to develop a physiologically based toxicokinetic model to describe methanol disposition in pregnancy. A multi-experimental approach addressed the goals of this project. Initial experiments characterized the systemic disposition of methanol after intravenous or oral administration to nonpregnant female rats. Methanol absorption from the gastrointestinal tract was rapid (peak concentrations appeared within 1 to 2 hours after administration) and essentially complete (systemic bioavailabilities ranged from approximately 0.6 to 1.0). As anticipated for short-chain aliphatic alcohols, methanol elimination from the systemic circulation was nonlinear due to saturation of the metabolic route or routes responsible for converting methanol to formaldehyde and, ultimately, formic acid. However, a significant parallel linear route of methanol elimination was observed, which accounted for an increasingly significant fraction of total elimination as methanol doses (or systemic concentrations) increased. The disposition of methanol after oral or intravenous administration was similar in pregnant and nonpregnant female rats, regardless of the gestational stage (day 7, 14, or 20 after conception) at which the toxicokinetics of methanol were examined. This observation indicated that data from nonpregnant subjects could be used in the development of the maternal portion of a comprehensive physiologic model for methanol disposition. Parallel experiments in female mice indicated that methanol elimination was approximately twice as rapid in mice as in rats due to a significantly higher maximal velocity for methanol metabolism in the smaller rodent species. As was the case in the rat, relatively small changes in methanol elimination were observed during the course of gestation in pregnant mice. In both species, the rate of methanol metabolism by fetal liver in vitro was less than 10% that of the metabolic rate in adult liver. The kinetics of methanol delivery into the fetal environment were examined by determining amniotic fluid concentrations of methanol after intravenous administration to pregnant rats. The net rate of methanol translocation from maternal blood to amniotic fluid decreased as methanol concentration increased. Although the mechanism of this anomalous result is unknown, it possibly is due to a methanol-induced decrease in blood flow to the fetus.
Pollack
G M
GM
University of North Carolina at Chapel Hill, School of Pharmacy, Beard Hall CB# 7360, Chapel Hill, NC 27599-7360, USA.
Brouwer
K L
KL
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001711:Biotransformation; D001822:Body Burden; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D066298:In Vitro Techniques; D019570:Inhalation Exposure / Q000009:adverse effects; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D018811:Maternal Exposure / Q000009:adverse effects*; D008657:Metabolic Clearance Rate; D000432:Methanol / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D015656:Respiratory Mechanics / Q000187:drug effects; D001335:Vehicle Emissions / Q000633:toxicity*
D001335:Vehicle Emissions; D000432:Methanol