Effects of Pregnancy on CYP3A and P-glycoprotein Activities as Measured by Disposition of Midazolam and Digoxin: A University of Washington Specialized Center of Research Study

Hebert, MF; Easterling, T.; Kirby, Brian J.; Carr, DB; Buchanan, ML; Rutherford, Tricia; Thummel, KE; Fishbein, DP; Unadkat, Jashvant D.

doi:10.1038/clpt.2008.1

Cited by 213 publications

(243 citation statements)

References 31 publications

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“…Similar drug concentration declines in pregnancy have also been reported for other CYP3A4 substrates,14, 15 and also in a previous case report for quetiapine 8. In that publication, trough serum levels of quetiapine in the first, second, and third trimester were 42%, 55%, and 53% lower than the nonpregnant levels, respectively.…”

Section: Discussionsupporting

confidence: 85%

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (−76%; confidence interval (CI), −83%, −66%; P < 0.001) and aripiprazole (−52%; CI, −62%, −39%; P < 0.001), but not for olanzapine (−9%; CI, −28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

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Section: Discussionsupporting

confidence: 85%

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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“…A lower recovery of unchanged drug in the urine was observed in our pregnant women compared with data reported for nonpregnant subjects (36% versus 59%), which is entirely consistent with the hypothesis that pregnancy shifts the major route of elimination for clonidine from the kidneys to organs involved in drug metabolism (Davies et al, 1977;Arndts, 1983). The enzymes involved in clonidine metabolism are currently unknown; however, pregnancy does increase the activities of CYP3A, CYP2D6, and CYP2C9 (Yerby et al, 1990;Tracy et al, 2005;Hebert et al, 2008). Clonidine is metabolized to five metabolites including the following: p-hydroxy-clonidine; dichlorophenylguanidine; 1-(2,6-dichloro-4-hydroxyphenyl)-guanidine; 2-[(2,6-dichlorophenyl)-imino]-imidazolidine-4-one; and 2-[2,6-dichloro-4-hydroxyphenyl)-imino]-imidazolidine-4-one (Darda et al, 1978).…”

Section: Clonidine Pharmacokinetics In Pregnancysupporting

confidence: 68%

Clonidine Pharmacokinetics in Pregnancy

Buchanan¹,

Easterling²,

Carr³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n ‫؍‬ 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 ؎ 168 ml/min during pregnancy compared with 245 ؎ 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r ‫؍‬ 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 ؎ 0.1 (arterial) and 1.0 ؎ 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.Chronic hypertension during pregnancy is associated with complications, including fetal growth restriction, premature birth, preeclampsia, placental abruption, hypertensive crisis, and in some cases fetal demise. Very little information is available on the pharmacokinetic changes that occur for antihypertensive medications during pregnancy. Clonidine, a centrally acting, ␣-2 adrenergic agonist, has been used for the treatment of hypertension during pregnancy (Kobinger, 1978;Hartikainen-Sorri et al., 1987). In the nonpregnant population, approximately 60% of clonidine is eliminated unchanged by the kidneys (Davies et al., 1977). There are significant changes in kidney function during pregnancy, with creatinine clearance reported to increase by 50 to 60% (Davison and Noble, 1981). The pharmacokinetics of clonidine have not been studied during pregnancy. The objective of this study was to characterize the pharmacokinetics of clonidine during pregnancy. Materials and MethodsAfter receiving written informed consent from patients, we examined steady-state pharmacokinetics of orally administered clonidine in the plasma of 17 pregnant women receiving clonidine during mid pregnancy (22-26 weeks gestation) or late pregnancy (34 -38 weeks gestation). Six of these women participated in maternal and umbilical cord (arterial and venous) plasma sample collections at the time of delivery for measurement of clonidine concentrations. Gestational age was based on the last menstrual period or early ultrasound dating.Subject Selection. This study was approved by the University of Washington Investigational Review Board. Subjects were eligible to participate if they were pregnant, 18 years of age, had a hematocrit Ն28%, and were receiving oral clonidine for maternal hypertension. Dosing Regi...

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“…However, no discernible differences in Mdr1 protein expression were observed between normal and pregnant mice (61). With respect to human patients, increases in the renal secretory clearances of metformin (62), amoxicillin (57), and digoxin (63) have been observed in pregnant females. The mechanism(s) for the increase in renal clearance is not known, but possible explanations include enhanced secretory transporter expression/function, decreased tubular reabsorption, and enhanced renal blood flow.…”

Section: Pregnancymentioning

confidence: 96%

Renal Transporters in Drug Development

Morrissey

Stocker

Wittwer

et al. 2013

Annu. Rev. Pharmacol. Toxicol.

279

277

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The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.

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Effects of Pregnancy on CYP3A and P-glycoprotein Activities as Measured by Disposition of Midazolam and Digoxin: A University of Washington Specialized Center of Research Study

Cited by 213 publications

References 31 publications

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Clonidine Pharmacokinetics in Pregnancy

Renal Transporters in Drug Development

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