Pregnancy-induced increase in metoprolol metabolism

Högstedt, Stellan; Lindberg, Bo; Peng, Dun Ren; Regårdh, C G; Rane, Anders

doi:10.1038/clpt.1985.114

Cited by 119 publications

(69 citation statements)

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“…First, up-regulation of CYP2D6 activity has been suggested as the mechanism for the observed gestational changes in the pharmacokinetics of several drugs, including metoprolol (Högstedt et al, 1985) and dextromethorphan (Wadelius et al, 1997). Enhanced hepatic CYP2D6 activity is consistent with our earlier observation of an approximate 80% increase in apparent oral clearance of clonidine in pregnant women compared with nonpregnant subjects (440 Ϯ 168 versus 245 Ϯ 72 ml/min, respectively) (Buchanan et al, 2009).…”

Section: Resultssupporting

confidence: 79%

CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance

Claessens¹,

Risler²,

Eyal³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Clonidine is a centrally acting, ␣-2 adrenergic agonist used for the treatment of hypertension during pregnancy. The metabolic pathways of clonidine are poorly understood, and the quantitative contribution of specific human cytochrome P450 (P450) isoforms has not been systematically assessed. In this study, 17 cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes-CYP2D6, 1A2, 3A4, 1A1, and 3A5-catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy. IntroductionClonidine [2-(2,6-dichloroanilino)-2-imidazoline] is an ␣-2 adrenergic agonist used extensively to treat hypertension. It is also used to treat withdrawal from opiate addiction, insomnia and Tourette's syndrome, and in conjunction with stimulants for the treatment of attention-deficit hyperactivity disorder (Dollery, 1991). By acting as a presynaptic ␣-2 receptor agonist in the brain, it inhibits the sympathetic outflow, causing lower heart rate and blood pressure (MacMillan et al., 1996).Clonidine has been used for the treatment of hypertensive disorders in pregnant women and is well tolerated by the mothers (Horvath et al., 1985). However, clinical observations indicate that higher doses or more frequent dosing of clonidine may be required during pregnancy (Buchanan et al., 2009). Consistent with those observations, we have recently found that apparent oral clearance of clonidine in pregnant women is 80% higher compared with that reported in the literature for men and nonpregnant women (Buchanan et al., 2009). The renal component of clonidine clearance remained unchanged as we described previously (Buchanan et al., 2009), suggesting that alteration in bioavailability and/or nonrenal clearance is responsible for the observed change in clonidine pharmacokinetics during pregnancy. Limited studies have suggested that oral drug absorption is not altered in pregnancy (Anderson, 2005), which leaves modulation of nonrenal clearance as a more likely explanation for the change in oral clonidine clearance in pregnancy. In nonpregnant subjects, approximately 60% of orally administered clonidine is cleared unchanged by the kidneys (Davies et al., 1977), with the remainder undergoing hepatic metabolism to produce inactive metabolites, mainly 4-hydroxyclonidine (Dollery, 1991). However, phase I metabolism of clonidine is poorly understood, and no attempt has been made to assess the role of drug-metabolizing cytochrome P450 (P450) enzymes in clonidine metabolism. The aim of this study was to determine the contribution of P450 enzymes toward the 4-hydroxylation of clonidine, which, in turn, could offer insight into the mechanism o...

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Section: Resultssupporting

confidence: 79%

CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance

Claessens¹,

Risler²,

Eyal³

et al. 2010

Drug Metab Dispos

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“…Therefore, an increase in hepatic metabolic activity will translate into increased first-pass metabolism after oral administration but will not appreciably change the systemic clearance of the drug. Numerous studies in the literature have demonstrated this pharmacokinetic principle, such as for metoprolol and propranolol (Herman et al, 1983;Hogstedt et al, 1983Hogstedt et al, , 1985.…”

Section: Cyp3a and P-gp In Pregnancy 1207mentioning

confidence: 99%

Changes in Pharmacokinetics of Anti-HIV Protease Inhibitors during Pregnancy: The Role of CYP3A and P-glycoprotein

Mathias¹,

Maggio‐Price²,

Lai³

et al. 2005

J Pharmacol Exp Ther

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Human immunodeficiency virus (HIV)-infected women have reduced exposure [area under the curve (AUC)] to anti-HIV protease inhibitors [e.g., nelfinavir (NFV)] during pregnancy. To determine the mechanistic basis of this phenomenon, we administered NFV mesylate orally (2.5 mg) or intravenously (0.625 mg) to timed pregnant (gestational age: 18 -19 days) and nonpregnant FVB mice. After oral but not after i.v. administration, the plasma clearance of NFV was higher (by 134%, p Ͻ 0.05) and bioavailability was lower (by 32%, p Ͻ 0.05) in pregnant (n ϭ 3) versus nonpregnant mice (n ϭ 3). These effects of pregnancy were not due to changes in plasma protein binding of NFV. The half-life of NFV depletion in hepatic S-9 fractions of pregnant mice (n ϭ 8) was 2.2-fold faster (p Ͻ 0.05) than that in nonpregnant mice (n ϭ 7). Hepatic CYP3A activity (testosterone 6␤-hydroxylation, n ϭ 4) and expression (n ϭ 8) were significantly higher (by 138 and 49%, p Ͻ 0.05) in pregnant mice than that in nonpregnant mice. In the intestine, no CYP3A activity was detected and CYP3A protein expression (n ϭ 6, p Ͼ 0.05) was not significantly different between the two groups. P-glycoprotein expression (n ϭ 6) in hepatic and intestinal tissue of pregnant mice was not significantly different from that in nonpregnant mice. These changes in disposition of NFV during pregnancy are predominately due to a change in its bioavailability. An increase in hepatic CYP3A can explain the reduced bioavailability of NFV during pregnancy. If such upregulation of hepatic CYP3A activity occurs in pregnant women, it has important implications for dose adjustment of a variety of drugs ingested by pregnant women and cleared predominately via CYP3A metabolism.

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“…Accumulating clinical evidence indicates that CYP2D6-mediated drug metabolism is increased in pregnant women compared with postpartum controls (Högstedt et al, 1985;Wadelius et al, 1997;Tracy et al, 2005). The underlying mechanisms remained unknown, in part because of a lack of experimental models that can recapitulate CYP2D6 induction during pregnancy.…”

Section: Interindividual Variability In Cyp2d6-mediated Drugmentioning

confidence: 99%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

151

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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Pregnancy-induced increase in metoprolol metabolism

Cited by 119 publications

References 1 publication

CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance

CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance

Changes in Pharmacokinetics of Anti-HIV Protease Inhibitors during Pregnancy: The Role of CYP3A and P-glycoprotein

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

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