CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences

Tamminga, Wim J.; Wemer, J.; Oosterhuis, B.; Wieling, Jaap; Wilffert, Bob; Leij, Lou de; Zeeuw, Rokus A. de; Jonkman, J. H. G.

doi:10.1007/s002280050615

Cited by 125 publications

(97 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

supporting

confidence: 86%

“…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.…”

supporting

confidence: 64%

See 1 more Smart Citation

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

Rodrigues¹,

Lü²

2004

Drug Metab Dispos

View full text Add to dashboard Cite

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...

show abstract

supporting

confidence: 86%

supporting

confidence: 64%

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

Rodrigues¹,

Lü²

2004

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Polymorphisms might explain some of the pharmacokinetic variability of voriconazole, in particular the unexplained variability in our model. It is unlikely that polymorphisms completely explain the observed variability, because the prevalence of poor metabolizers of CYP2C19, who likely contribute most to the variability in voriconazole trough concentrations between patients, is only 3% to 5% in the Caucasian population (26).…”

Section: Discussionmentioning

confidence: 99%

Inflammation Is Associated with Voriconazole Trough Concentrations

Wanrooy

Span

Rodgers

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The Swedish females taking oral contraceptives had lower CYP2C19 activity as compared to women without. Tamminga et al have also describes an effect of OCs using S-mephynotoin as a probe drug [26]. The oral contraceptives may contain progestin with or without ethinyl oestradiol and it is not known whether it is the oestrogen or the progestin component that inhibits drug metabolism [10].…”

Section: Discussionmentioning

confidence: 99%

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

Ramsjö

Aklillu

Bohman

et al. 2010

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Objectives To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use and smoking habit.Methods CYP2C19 activity was determined in 185 healthy Swedish and 150 Korean subjects as omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay.Results As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared to Swedes (3.8%) and the frequency of the CYP2C19*17 allele was very low in Koreans 0.3%. Among subjects homozygous for CYP2C19*1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p<0.000001). Interestingly in Koreans a pronounced gender difference was apparent: females (n=24) had significantly lower MR than males (N=30) (p<0.0001) but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p<0.00001), whereas OC was only used by one Korean. No effect of smoking was observed. ConclusionsWe find specific gender dependent effects of CYP2C19 activity in Koreans but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.

show abstract

CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences

Cited by 125 publications

References 13 publications

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

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

Inflammation Is Associated with Voriconazole Trough Concentrations

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

Contact Info

Product

Resources

About