Increased 6-Hydroxycortisol Excretion in Pregnant Women: Implication of Drug-Metabolizing Enzyme Induction

Ohkita, C; Goto, Mitsuyoshi

doi:10.1177/106002809002400902

Cited by 26 publications

(22 citation statements)

References 18 publications

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“…In this population, we found that the oral clearance of MDZ is significantly increased during pregnancy , suggesting that hepatic and/or intestinal CYP3A activity is increased during pregnancy. This conclusion is supported by other data in the literature that also suggest increased CYP3A activity during human pregnancy (Rey et al, 1979;Ohkita and Goto, 1990;Kosel et al, 2003;Tracy et al, 2005). The discrepancy between humans and macaques may be due to differences in the intrinsic rate of MDZ metabolism in the two species.…”

Section: Discussionsupporting

confidence: 81%

Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina

Zhang

Chung

et al. 2009

J Pharmacol Exp Ther

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Plasma concentrations of protease inhibitors are lower in pregnant women than in nonpregnant women or men. Using nelfinavir as a model protease inhibitor, we have shown that this phenomenon can be reproduced in a representative non-human primate model, Macaca nemestrina (J Pharmacol Exp Ther 329: 1016 -1022, 2009). Nelfinavir is cleared from the body predominantly by CYP3A metabolism and P-glycoprotein (P-gp) efflux. Therefore, using midazolam (MDZ) as a CYP3A probe and digoxin (DIG) as a P-gp probe, we determined the antepartum (73-118 days) and postpartum (61-130 days) in vivo intestinal and hepatic CYP3A or P-gp activity in the macaque. Although the systemic clearance of MDZ was significantly increased (ϳ70%) during pregnancy after intra-arterial (IA) administration of the drug ( 15 N-labeled MDZ; 40 g/kg), pregnancy did not affect the oral clearance of the drug administered simultaneously (1 mg/kg p.o.) with the IA dose. In vitro studies in hepatic and intestinal S-9 fractions indicated no effect of pregnancy on CYP3A activity or protein expression in the small intestine or liver. In contrast, neither the oral (100 g/kg) nor the IA (10 g/kg) clearance of DIG was significantly altered by pregnancy, indicating no effect of pregnancy on P-gp activity. Assuming that MDZ and DIG are selective substrates of the macaque CYP3A enzymes and P-gp, respectively, these results suggest that factors other than increased CYP3A or P-gp activity contribute to the increased clearance of protease inhibitors during M. nemestrina pregnancy.

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Section: Discussionsupporting

confidence: 81%

Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina

Zhang

Chung

et al. 2009

J Pharmacol Exp Ther

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“…However, pregnancy is associated with many physiological changes, which may have an impact on the pharmacokinetics of drugs 15,16. Thus, it is of value to study the pharmacokinetic properties of antimalarial drugs in this special group of patients to determine whether adjustment of dose or dose regimen is necessary.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Piperaquine in Pregnant Women in Sudan with Uncomplicated Plasmodium falciparum Malaria

Adam¹,

Tärning²,

Mahgoub³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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The pharmacokinetic properties of piperaquine were investigated in 12 pregnant and 12 well-matched, non-pregnant women receiving a three-day oral fixed dose combination regimen of dihydroartemisinin and piperaquine for treatment of uncomplicated Plasmodium falciparum at New Halfa Hospital in eastern Sudan. Frequent venous plasma samples were drawn from the patients over a 63-day period and a complete concentration–time profile was collected for 7 pregnant and 11 non-pregnant patients. Piperaquine was quantified using a liquid chromatography–mass spectrometry/mass spectrometry method. Pregnant women had a significantly higher total drug exposure (median area under the curve [range] = 1,770 [1,200–5,600] hr × ng/mL versus 858 [325–2,370] hr × ng/mL; P = 0.018) and longer time to maximal concentration (4.00 [1.50–4.03] hr versus 1.50 [0.500–8.00] hr; P = 0.02) after the first dose compared with non-pregnant women. There was no other significant difference observed in piperaquine pharmacokinetics between pregnant and non-pregnant women, including no difference in total drug exposure or maximum concentration. The overall pharmacokinetic properties of piperaquine in this study were consistent with previously published reports in non-pregnant patients.

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“…Other evidence suggesting a hormonal influence on CYP3A activity exists in pregnancy. 6β‐hydroxycortisol:cortisol ratios have been found to increase 300% in the third trimester of pregnancy and return to baseline within 3 months after delivery [9].…”

Section: Introductionmentioning

confidence: 99%

Poor correlation between 6β‐hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity

Chen

Gotzkowsky

Nafziger

et al. 2006

Brit J Clinical Pharma

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AimsA non-invasive proposed method for measuring CYP3A activity is the urinary 6 β -hydroxycortisol:cortisol ratio. This ratio has been used as an indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor. MethodsThis was a sequential, cross-over study design. Intravenous midazolam 0.025 mg kg − 1 was administered to 10 male and 10 female subjects once every 14 days for 4 months. Fluvoxamine 150 mg day − 1 was given to all subjects during the last two visits. Total body clearance of midazolam and urinary 6 β -hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity. ResultsNo significant correlations were found between these two markers ( r 2 < 0.5, P > 0.05). Larger interindividual and intra-individual variability in CYP3A activity was observed in 6 β -hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately 1.5-fold and cortisol ratios decreased approximately 1.9-fold. ConclusionsThe high intra-individual variability of the urinary cortisol ratio, compared with midazolam, makes this a suboptimal CYP3A phenotyping tool.

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Increased 6-Hydroxycortisol Excretion in Pregnant Women: Implication of Drug-Metabolizing Enzyme Induction

Cited by 26 publications

References 18 publications

Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina

Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina

Pharmacokinetics of Piperaquine in Pregnant Women in Sudan with Uncomplicated Plasmodium falciparum Malaria

Poor correlation between 6β‐hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity

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