Metabolism and Disposition of Bupropion in Pregnant Baboons (Papio cynocephalus)

Abstract

Recent in vitro data obtained in our laboratory revealed similarities between baboons and humans in the biotransformation of bupropion (BUP) by both hepatic and placental microsomes. These data supported the use of baboons to study BUP biotransformation during pregnancy. The aim of this investigation was to determine the pharmacokinetics of BUP in baboons during pregnancy and postpartum, as well as fetal exposure to the drug after intravenous administration. Pregnant baboons (n = 5) received a single intravenous bolus dose of bupropion hydrochloride (1 mg/kg) at gestational ages 94-108 days (midpregnancy), 142-156 days (late pregnancy), and 6 weeks postpartum. Blood and urine samples were collected for 12 and 24 hours, respectively. The concentrations of BUP, hydroxybupropion (OH-BUP), threohydrobupropion, and erythrohydrobupropion in plasma were determined by liquid chromatography-tandem mass spectrometry. Relative to the postpartum period, the average midpregnancy clearance of BUP trended higher (3.6 6 0.15 versus 2.7 6 0.28 l/h per kg) and the average C max (294 6 91 versus 361 6 64 ng/ml) and the area under the curve (AUC) of BUP values (288 6 22 versus 382 6 42 h·ng/ml) trended lower. AUC OH-BUP also tended to be lower midpregnancy compared with postpartum (194 6 76 versus 353 6 165 h·ng/ml). Whereas the observed trend toward increased clearance of BUP during baboon pregnancy could be associated with a pregnancy-induced increase in its biotransformation, the trend toward increased renal elimination of OH-BUP may overshadow any corresponding change in the hydroxylation activity of CYP2B.

The baboon (Papio sp.) as a model for female reproduction studies

“…Baboons have already been used on a wide variety of reproductive studies, including pregnancy [40, 41, 42, 43,] fetal development [44, 45,] pharmacokinetics of compounds in pregnancy [46, 47,] abortifactant drugs [48,]nutrient restriction and the maternal/fetal relationship [49,] genetics [50,] endometriosis [51, 52,] hormonal [14, 16, 21, 53, 54, 55, 56,] temporary contraception [57, 58,] embryonic stem cells and ART [13,] pathology [59, 60,] and permanent contraception [18.] Their temperament and similarities to human anatomy warrant their continued use for reproductive studies.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…For example, recent progress has been made to establish the pregnant baboon as a non-human primate model for pharmacokinetic investigations. 459,460,461,462,463,464 There is also a need to refine the pool of potential placental targeting moieties in order to minimize off-target nanoparticle distribution. Side effects can be averted when the disbursement of medication to off-target sites is reduced.…”

Placental Transfer of Antidepressant Medications: Implications for Postnatal Adaptation Syndrome

“…While rat and mice models do provide information about transplacental transfer of medications, the placenta is the most species-specific organ and therefore non-human primates models (baboons, rhesus macaques) offer the greatest insight into human transplacental drug transport [39]. Currently, only one study has used a non-human primate to investigate transplacental drug transport of antidepressant medications [23]. Animal models allow researchers to determine the maximum fetal exposure as well as how quickly the exposure occurs after a maternally ingested single dose [28, 40, 41].…”

“…However, in comparison to the liver, the activity of these enzymes in the placenta is relatively low and thought to have a minor role in affecting drug levels [18]. Of the CYPs involved in the metabolism of antidepressant medications (Table 2), only CYP3A4, CYP1A2, CYP2B6 have been identified in the human placenta [19-23]. CYP3A4 has been identified at both the mRNA and protein level [13, 22], while only mRNA expression has been identified for CYP1A2 [19-21].…”

“…There is a general trend for increased expression of mRNA and protein as well as activity of CYPs to decrease as pregnancy progresses potentially leading to greater drug exposure towards the end of pregnancy (Table 1) [13, 18]. However, there is no research aside for CYP2B6 for bupropion [23, 24], to confirm CYP activity leads to placental metabolism of antidepressants during pregnancy. Therefore, conclusions about the extent to which this mechanism relates to fetal exposure are not possible.…”