Morphine Metabolism in the Pregnant Guinea Pig and Her Pups

Abstract

The study of chronic in utero exposure to heroin and morphine in the human is limited by polysubstance abuse. The guinea pig was used as a model for the human to determine the in vivo and in vitro effect of chronic morphine exposure on morphine metabolism in the pregnant dam and her offspring. In vivo pharmacokinetics of morphine were examined in pregnant guinea pigs following pretreatment with either saline or morphine. In vitro hepatic enzyme kinetics were also examined in a similar group of pregnant dams and their fetuses. Additional pregnant dams were allowed to give birth and their pups’ enzyme kinetics were studied at 1, 3, and 7 days. Apparent V_MAX for the formation of both morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation was significantly increased in the morphine-treated pregnant guinea pig. However, no effect of morphine treatment was detectable on the in vivo pharmacokinetics of morphine in the pregnant dam. The apparent morphine K_M for the formation of M3G was significantly different than the apparent K_M for the formation of M6G. Significant age effects on the enzyme kinetics were found. The apparent V_MAX for the formation of both glucuronides increased through the neonatal period. Through literature comparisons, the guinea pig was shown to have in vivo pharmacokinetics similar to the pregnant human, and the guinea pig pups were found to have enzyme development consistent with in vivo pharmacokinetic development seen in human neonates, infants and children.

The Contribution of Fetal Metabolism to the Disposition of Morphine

“…In pregnant guinea pigs, chronic morphine exposure increased enzyme activity in vitro but not in vivo. Morphine exposure did not affect fetal or newborn metabolic activity (Smith et al, 1999). In the present study, all animals were exposed to morphine postoperatively for several days to provide analgesia.…”

Respiratory effects of chronic in utero methadone or morphine exposure in the neonatal guinea pig

“…Importantly, the elimination half-life of methadone is 15 hrs in the pregnant guinea pig [37] which is comparable to that in humans [16,36,41]. In contrast, the elimination half-life of morphine in the pregnant guinea pig is 1.3 hr [40]. Consequently, daily administration of methadone would be more prone to drug accumulation than morphine requiring different doses for the two drugs in a model of once daily drug administration over a long period of time.…”

“…Consequently, daily administration of methadone would be more prone to drug accumulation than morphine requiring different doses for the two drugs in a model of once daily drug administration over a long period of time. Finally, human infants and guinea pig pups, unlike rat or mouse pups, metabolize morphine to both pharmacologically active metabolites, M3G and M6G [23,40], making the guinea pig an excellent model for the present study.…”

“…The guinea pig was chosen because, like humans, guinea pigs have a hemomonochorial placenta and unlike rat or mouse pups, guinea pig pups metabolize morphine to both its major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in similar quantities to human infants [23,40]. Moreover, we have previously shown that acute methadone treatment is more potent, with regard to respiratory disturbances, than morphine in the newborn guinea pig [30] and that chronic in utero morphine exposure increases locomotor activity and causes hyperventilation during the first week of life [14].…”

“…We hypothesize that in utero methadone exposure will result in similar locomotor and respiratory disturbances. However, due to its long elimination half-life in pregnant guinea pigs [37], we expect methadone-induced changes to be of slower onset and longer duration than morphine whose elimination half-life is about one tenth as long, while both values are comparable to pregnant human subjects [16,36,40,41].…”