Impairment of Diazepam Metabolism by Low-Dose Estrogen-Containing Oral-Contraceptive Steroids

Abernethy, Darrell R.; Greenblatt, David J.; Divoll, Marcia; Arendt, R; Ochs, H R; Shader, Richard I.

doi:10.1056/nejm198204013061307

Cited by 96 publications

(25 citation statements)

References 10 publications

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“…In the same study, the ratio of (S)-mephenytoin to (R)-mephenytoin in urine (S/R ratio) increased from 0.11 to 0.28, and the effect was similar to that observed with subjects genotyped CYP2C19*1/*2 (versus CYP2C19*1/*1). A comparable change in the S/R ratio has been reported by Hagg et al (2001) and Tamminga et al (1999).EE-containing OC formulations have also been shown to affect the PK and metabolism of diazepam, propranolol, proguanil, and selegiline (Abernethy et al, 1982;Walle et al, 1996;Laine et al, 1999;McGready et al, 2003). All four drugs are reported to be CYP2C19 substrates.…”

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confidence: 65%

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IS 17α-Ethinyl ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19?

Rodrigues¹,

Lü²

2004

Drug Metab Dispos

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We have read with great interest the increasing number of publications reporting that oral contraceptive (OC) 1 formulations can decrease CYP2C19 activity. For example, Palovaara et al. (2003) evaluated the effect of two OC formulations on the hydroxylation of omeprazole. One formulation contained EE (40 g) and LNG (60 g), whereas the second contained LNG (60 g) and was devoid of EE. The combination of EE and LNG increased both the area under the plasma concentration vs. time curve of omeprazole (38%) and the omeprazole to 5-hydroxy omeprazole area under the plasma concentration vs. time curve ratio (48%). LNG alone had no affect on the PK and metabolism of omeprazole. In addition, neither formulation inhibited CYP3A4-catalyzed omeprazole sulfone formation. Because the hydroxylation of omeprazole is widely accepted as an index of CYP2C19 activity (Chang et al., 1995;Lasker et al., 1998;Abelo et al., 2000;Kita et al., 2001), the authors concluded that OC preparations containing EE decrease CYP2C19 activity. The observations of Palovaara et al. (2003) confirm the findings of Laine et al. (2000), who also reported an increase (ϳ100%) in the omeprazole to 5-hydroxy omeprazole ratio in plasma. In the same study, the ratio of (S)-mephenytoin to (R)-mephenytoin in urine (S/R ratio) increased from 0.11 to 0.28, and the effect was similar to that observed with subjects genotyped CYP2C19*1/*2 (versus CYP2C19*1/*1). A comparable change in the S/R ratio has been reported by Hagg et al. (2001) and Tamminga et al. (1999).EE-containing OC formulations have also been shown to affect the PK and metabolism of diazepam, propranolol, proguanil, and selegiline (Abernethy et al., 1982;Walle et al., 1996;Laine et al., 1999;McGready et al., 2003). All four drugs are reported to be CYP2C19 substrates. However, the effect of EE on their PK cannot be ascribed to CYP2C19 alone, because other cytochromes P450 are involved in metabolism (Jung et al., 1997;Yang et al., 1999;McGinnity et al., 2000;Hidestrand et al., 2001). The same cannot be said for the urinary mephenytoin S/R ratio and the omeprazole to 5-hydroxy omeprazole ratio in plasma. Both have served as a useful index of CYP2C19 activity and have been validated with genotyped subjects (Rodrigues and Rushmore, 2002).Although the results of these various clinical drug interaction studies are compelling, it cannot be assumed that EE is a clinically relevant inhibitor of CYP2C19. The dose of EE is low (30 -50 g), and peak plasma concentrations (total EE) range between 0.6 and 0.7 nM (Belle et al., 2002). Moreover, Jurima et al. (1985) have reported that EE itself is a weak inhibitor (K i ϳ100 M) of human liver microsomal mephenytoin (racemate) hydroxylase activity, whereas Laine et al. (2003) observed inhibition (70%) of omeprazole 5-hydroxylation only at a high concentration of EE (0.1 mM). We have also determined that EE is a relatively weak, reversible inhibitor (IC 50 ϭ 19 M) of CYP2C19 (4Ј-hydroxylation of (S)-mephenytoin) in human liver microsomes. The IC 50 was determined at the...

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supporting

confidence: 65%

“…EE-containing OC formulations have also been shown to affect the PK and metabolism of diazepam, propranolol, proguanil, and selegiline (Abernethy et al, 1982;Walle et al, 1996;Laine et al, 1999;McGready et al, 2003). All four drugs are reported to be CYP2C19 substrates.…”

mentioning

confidence: 99%

IS 17α-Ethinyl ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19?

Rodrigues¹,

Lü²

2004

Drug Metab Dispos

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“…The disposition of diazepam was compared in eight women using combined OCs with 50 mg ethinyloestradiol and eight women not using OCs [17]. The mean elimination half-lives of diazepam were 69 h and 47 h, respectively.…”

Section: Discussionmentioning

confidence: 99%

Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers

Hägg¹,

Spigset

Dahlqvist³

2001

Br J Clin Pharmacol

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Aims The study was carried out in order to assess the effects of gender and the use of oral contraceptives (OCs) on CYP2D6 and CYP2C19 activities in healthy volunteers. Methods Six hundred and eleven Caucasian volunteers (330 males and 281 females; age range 18±49 years) were phenotyped with respect to CYP2D6 and CYP2C19 by means of the probe drugs dextromethorphan and mephenytoin, respectively. Extensive metabolisers were selected for this study. Results The median dextromethorphan/dextrorphan metabolic ratio in non-OC using females was signi®cantly lower than in males (0.067 vs 0.080; P=0.033) (mean difference in ln dextromethorphan/dextrorphan metabolic ratio 0.023, 95% CI 0.03±0.43). For the mephenytoin S/R ratio, no such difference was observed. However, OC using females had a signi®cantly higher median mephenytoin S/R ratio than non-OC using females (0.230 vs 0.090; P<0.001) (mean difference in ln mephenytoin S/R ratio 0.082, 95% CI 0.60±1.04). Moreover, females using combined OCs had a signi®cantly higher median ratio than females using OCs with progestins only (median 0.258 vs 0.135; P=0.008) (mean difference in ln mephenytoin S/R ratio 0.82, 95% CI 0.21±1.34). Conclusions Given certain assumptions, the study indicates that females in the fertile age have a slightly higher CYP2D6 activity compared with males. There was no evidence of a gender difference in CYP2C19 activity. The use of combined OCs reduces the activity of CYP2C19, an effect that seems to be related to the ethinyloestradiol component.

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“…mean) pre-dose 08.00 h plasma cortisol concentrations are approximately twofold higher in oral contraceptive users (416 (30) ng/ml) than in control subjects (212 (31) ng/ml; P < 0.001). The direction of the changes in the parameters of prednisolone disposition as a result of dose and oral contraceptive use are summarised in Table 3 (Fernandez-Pol & Zaninovich, 1975), chlordiazepoxide (Roberts et at., 1979), caffeine (Patwardhan et at., 1980), and phenytoin (Abernathy et at., 1982 (Boekenoogen et at., 1983). …”

Section: Dosementioning

confidence: 99%

Alterations in prednisolone disposition as a result of oral contraceptive use and dose.

Meffin¹,

Wing²,

Sallustio³

et al. 1984

Brit J Clinical Pharma

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1 The disposition of total and free prednisolone has been studied in eight female subjects who used combined oestrogen-progestogen oral contraceptives and in eight female subjects who did not, each of whom received separate intravenous doses of 0.1 mg/kg (low) and 1.0 mg/kg (high) of prednisolone. 2 Mean free prednisolone clearance was reduced -30% in oral contraceptive users compared to control subjects (P < 0.001), the difference being greater for the low dose (39%) than for the high dose (24%). Pre-dose plasma cortisol concentrations were elevated two-fold (P < 0.001) in oral contraceptive users compared to control subjects. These effects are consistent with a mechanism in which the competitive inhibition of free prednisolone clearance by cortisol contributes to the reduction of free prednisolone clearance by oral contraceptive use. 3 Mean total prednisolone clearance and steady state distribution volume showed an approximate two-fold dose dependent increase consistent with a similar increase in plasma prednisolone free fraction (P < 0.001). Free prednisolone clearance showed an 18% dose dependent decrease (P < 0.001) but free steady-state distribution volume did not change with dose. 4 At plasma prednisolone concentrations < 400 ng/ml, prednisolone free fractions at any prednisolone concentration were greater after the low, than after the high dose. This effect is consistent with the displacement of prednisolone by cortisol from transcortin but not from albumin.

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Impairment of Diazepam Metabolism by Low-Dose Estrogen-Containing Oral-Contraceptive Steroids

Cited by 96 publications

References 10 publications

IS 17α-Ethinyl ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19?

IS 17α-Ethinyl ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19?

Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers

Alterations in prednisolone disposition as a result of oral contraceptive use and dose.

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