A recent FDA warning on the use of caffeine during pregnancy and the current prolonged use of methylxanthines in premature infants for the treatment of apnea serve to focus current concern over the potential deleterious effects of these agents during development. Past investigations into the effects of fetal exposure have been limited to morphologic endpoints. None has carefully related the effects to pharmacokinetic disposition of the drug. It is our hypothesis that significant long-term growth and behavioral disturbances are produced by exposure of the rapidly developing brain to drugs with known effects on both cell metabolism and behavior. We propose to conduct investigations into the effects of methylxanthine exposure on growth and behavioral development in an animal model. We have previously characterized a rabbit model closely correlated with human behavioral state development and have described an automated method for quantification of behavioral data reflecting CNS maturation. Brief postnatal exposure of the newborn to theophylline or caffeine results in marked and prolonged alterations in behavioral development and growth. We plan to administer caffeine to rabbits during pregnancy by two routes: 1) an implantable infusion pump which will maintain steady-state drug levels and 2) oral ingestion via drinking water, simulating pulsed dietary intake by pregnant women. Mothers and fetuses receiving caffeine by infusion will be pharmacokinetically characterized and growth parameters will be determined. Separate animals dosed by both me nods will be allowed to give birth normally and the offspring will be measured for the distribution of their sleep and wake states from Day 1 through Day 40. Some of these offspring will then be sacrificed and subjected to drug level and growth determinations, while others will be set aside and followed into adulthood where other behavioral measures will be obtained to evaluate the long-term effects of caffeine. In addition, we shall administer caffeine and theophylline postnatally to rabbit pups and characterize behavioral development, pharmacokinetics, and growth parameters using similar techniques. We expect our techniques for drug administration, behavioral characterization and pharmacokinetic analysis to become widely applicable to future studies of the embryopathic and behavioral effects of drugs and other chemicals during pregnancy.
| Dorrbecker, S H; Kramer, P A; Dorrbecker, B R et al. (1988) Caffeine disposition in the pregnant rabbit. II. Fetal distribution of caffeine and paraxanthine during chronic maternal caffeine administration. Dev Pharmacol Ther 11:118-24 |
| Dorrbecker, S H; Raye, J R; Dorrbecker, B R et al. (1988) Caffeine disposition in the pregnant rabbit. I. Pharmacokinetics following administration by intravenous bolus and continuous zero-order infusion. Dev Pharmacol Ther 11:109-17 |
| Dorrbecker, S H; Ferraina, R A; Dorrbecker, B R et al. (1987) Caffeine and paraxanthine pharmacokinetics in the rabbit: concentration and product inhibition effects. J Pharmacokinet Biopharm 15:117-32 |
