Pharmacokinetics of metoprolol during pregnancy and lactation

Abstract

The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25–750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.

Pharmacokinetics of Bupropion and Its Pharmacologically Active Metabolites in Pregnancy

“…Nevertheless, it appears that decreased activity of CYP2C19 due to pregnancy, along with loss-of-function variants of CYP2C19, could contribute to higher steady-state exposure to TB and EB during pregnancy. The TB and EB metabolites of BUP have an inhibitory effect on the CYP2D6 enzyme (Parkinson et al, 2010), which is upregulated during pregnancy (Ke et al, 2013;Ryu et al, 2016). Therefore, possible drug-drug interactions of BUP and CYP2D6 substrates cannot be discounted in pregnancy, particularly in instances when dose adjustment of CYP2D6-metabolized medications is considered (Ryu et al, 2016).…”

Pregnancy‐related pharmacokinetic changes

“…The physiologic changes that occur during pregnancy result in altered drug disposition and response to many medications. Pregnancy alters apparent drug metabolizing enzyme activity, renal filtration, apparent renal drug transporter activity, protein binding, and volume of distribution . However, dosage adjustments based on pharmacokinetic changes during pregnancy must take into account alterations in pharmacodynamics as well as maternal, fetal, and neonatal safety .…”

Safe and Effective Use of Pharmacologic and Device Therapy for Peripartum Cardiomyopathy

“…Carvedilol exhibits high protein binding, which may limit fetal exposure, but β 2 ‐mediated antitocolytic activity may occur during pregnancy . No fetal malformations have been attributed to metoprolol tartrate, which crosses the placenta, in patients with maternal hypertension or tachycardia . There are limited data with the succinate salt .…”

“…No fetal malformations have been attributed to metoprolol tartrate, which crosses the placenta, in patients with maternal hypertension or tachycardia . There are limited data with the succinate salt . Whereas β‐blockers are frequently used during pregnancy for management of hypertension without evidence of teratogenic effects, reports have been published describing fetal adverse effects attributed to β‐blockers, such as intrauterine growth retardation, bradycardia, hypoglycemia, hypothermia, and respiratory depression .…”

“…Product labeling of ACEIs and ARBs caution use during breastfeeding, but case reports demonstrate insignificant risks with select ACEIs . The three β‐blockers used for HF (bisoprolol, carvedilol, and metoprolol succinate) should be compatible with breastfeeding, although most data are with metoprolol . Similarly, aldosterone antagonists are reported to be acceptable .…”