Influence of ethinylestradiol-containing combination oral contraceptives with gestodene or levonorgestrel on caffeine elimination

Balogh, A; Klinger, G; Henschel, L; Börner, A.; Vollanth, R; Kuhnz, W.

doi:10.1007/bf00192743

Cited by 63 publications

(58 citation statements)

References 14 publications

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“…Increased sex steroids associated with pregnancy may modulate several of the CYP450 and UGT isoforms in a clinically relevant manner. Synthetic analogs of sexsteroids associated with pregnancy, such as those used in hormone replacement therapy or oral contraceptives, modulate several CYP450 isoforms via inhibition (CYP1A2, 26 CYP2C19, 27 CYP2B6, 28 and CYP3A4 29 ), induction (CYP2A6 30 ), or increasing glucuronidation by UGT1A4 and possibly UGT2B7. 31,32 Cytochrome P450 and UGT changes may also have effects on adverse effect burden for both mother and fetus/infant because drug exposure partially depends on metabolism.…”

Section: Resultsmentioning

confidence: 99%

Pharmacotherapy for Mood Disorders in Pregnancy

Deligiannidis¹,

Byatt

Freeman³

2014

Journal of Clinical Psychopharmacology

160

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Objective Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations. Methods The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period. Results Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period. Conclusions Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.

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Section: Resultsmentioning

confidence: 99%

Pharmacotherapy for Mood Disorders in Pregnancy

Deligiannidis¹,

Byatt

Freeman³

2014

Journal of Clinical Psychopharmacology

160

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“…Both tizanidine and MEL are low oral bioavailability (Ͻ25%) CYP1A2 substrates because of first-pass metabolism (Härtter et al, 2001;Granfors et al, 2005). Although caffeine and theophylline also serve as CYP1A2 substrates, they undergo minimal first pass, are highly bioavailable, and the impact of EE is less marked (ϳ40% decrease in clearance) (Roberts et al, 1983;Balogh et al, 1995). Despite these clinical data, it is only very recently that assessment of CYP1A2 inhibition in vitro has been described previously (Karjalainen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Further Assessment of 17α-Ethinyl Estradiol as an Inhibitor of Different Human Cytochrome P450 Forms in Vitro

Chang¹,

Chen²,

Yang³

et al. 2009

Drug Metab Dispos

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ABSTRACT:17␣-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC 50 Reports continue to appear describing drug interactions involving oral contraceptive (OC) formulations containing 17␣-ethinyl estradiol (EE). For example, Hilli et al. (2008) reported recently that melatonin (MEL) area under the plasma concentration versus time curve (AUC) is increased (ϳ5-fold), and the 6-hydroxy melatonin (MEL 6-OH)/ MEL AUC ratio is decreased (88%). CYP1A2 is known to play a major role in the metabolism of MEL in human liver microsomes (HLM), so the authors deduced that the enzyme was the locus of the interaction (Facciolá et al., 2001;Härtter et al., 2001;Ma et al., 2005). EE-containing OCs exert a similar effect on the pharmacokinetics (PK) of tizanidine (Granfors et al., 2005). Both tizanidine and MEL are low oral bioavailability (Ͻ25%) CYP1A2 substrates because of first-pass metabolism (Härtter et al., 2001;Granfors et al., 2005). Although caffeine and theophylline also serve as CYP1A2 substrates, they undergo minimal first pass, are highly bioavailable, and the impact of EE is less marked (ϳ40% decrease in clearance) (Roberts et al., 1983;Balogh et al., 1995). Despite these clinical data, it is only very recently that assessment of CYP1A2 inhibition in vitro has been described previously (Karjalainen et al., 2008). In fact, Karjalainen et al. (2008) reported EE as a relatively weak inhibitor of phenacetin O-deethylation (POD) activity in HLM (low K m component; IC 50 ϭ 24 M).Drug interactions with EE-containing OC formulations have also included a number of CYP2C19 substrates, such as omeprazole, mephenytoin, and proguanil (Hägg et al., 2001; Rodrigues and Lu, 2004, references therein;Shelepova et al., 2005). Likewise, drug interactions with imipramine and selegiline have been described previously (Abernethy et al., 1984;Laine et al., 1999). The latter is a CYP2B6 and CYP2C19 substrate, also with a low oral bioavailability (Ͻ10%), and greater than 10-fold increases in AUC have been reported with OCs (Laine et al., 1999;Benetton et al., 2007). More importantly, the contribution of CYP2C19 after oral dosing of selegiline is thought to be minimal (Laine et al., 2001). Although CYP2B6 is implicated, there are no reports describing the impact of CYP2B6 genotype (or phenotype) on the oral PK of selegiline, and its contribution in vivo is not known. Moreover, the clinical drug interaction between EE and a CYP2B6 probe (bupropion) is not significant despite evidence for mechanism-based inhibition in vitro Palovaara et al., 2003). The same can also be said for the observed mechanism-based inhibition of CYP3A4 and CYP3A5 in vitro because the effect of EE on the PK of CYP3A substrates (e.g., midazolam and nifedipine) is minimal (Balogh et al., 1998; Article, publication date, and citation information c...

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“…However, the hormone concentrations used in vitro exceed those found in clinical settings of OCs or HRT by several fold. Nevertheless, the balance of evidence suggests that concomitantly administered OCs can inhibit CYP1A2, 2C19 and 3A4 in vivo [8,9,10,13], but there are also studies that suggest lack of such effect with regard to CYP1A2 and 3A4 [16,17]. The different effects of OCs and HRT have been demonstrated for CYP3A4, as OCs containing ethinylestradiol and gestodene inhibited the CYP3A4-mediated 1-hydroxylation of midazolam in healthy volunteers [13], while HRT had no effect on midazolam pharmacokinetics [14].…”

Section: Discussionmentioning

confidence: 96%

“…In vitro experiments show an inhibitory effect of ethinylestradiol and some synthetic progestines such as gestodene on CYP-mediated metabolism [5,6,7], and some clinical trials indicate that oral contraceptives (OCs) inhibit the oxidative drug metabolism in vivo [8,9,10]. It has been shown in four women that concomitant use of OCs containing ethinylestradiol and either gestodene or levonorgestrel and selegiline resulted in 10-to 20-fold increase in the bioavailability of selegiline, which finding was consistent at four different dose levels from 5 mg to 40 mg [11].…”

Section: Introductionmentioning

confidence: 99%