Influence of repeated oral doses of ethinyloestradiol on the metabolic disposition of [ 13 C 2 ]-ethinyloestradiol in young women

Kuhnz, W.; Hümpel, M.; Biere, H.; Gross, Dennis M.

doi:10.1007/s002280050098

Cited by 10 publications

(10 citation statements)

References 8 publications

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“…Although they are CYP3A inhibitors, they were located here because they inhibit CYP3A directly, not in a metabolism-based manner. Ethynylestradiol, which is located in zone 2, is a potent metabolism-based inhibitor, but it does not cause in vivo DDI because of its usually low blood concentrations of Յ1 nM dmd.aspetjournals.org (Kuhnz et al, 1996;Palovaara et al, 2000). Compounds reported to cause both MBI and significant in vivo DDIs, such as diltiazem, verapamil, clarithromycin, erythromycin, mibefradil, and nefazodone, were mainly located in zone 3.…”

Section: Discussionmentioning

confidence: 99%

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Watanabe

Nakamura²,

Okudaira³

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:The CYP3A family is a major drug metabolism enzyme in humans. Metabolism-based inhibition of CYP3A might cause clinically significant drug-drug interactions (DDIs). To assess the risk of DDIs caused by metabolism-based inhibition (MBI) of CYP3A, we established an automated single time-and concentration-dependent inhibition assay. To create a diagram to assess DDI risk of compounds in the early discovery stage, we classified 171 marketed drugs by the possibility of the occurrence of in vivo DDI caused by MBI from the relationship between the inactivation activity determined in the MBI screening, the therapeutic blood or plasma concentration, and the in vivo DDI information. This analysis revealed that the DDI risk depends on both the MBI potential and the blood concentration of a compound, and provided the criteria of the DDI risk. In the assay, three compounds (midazolam, nifedipine, and testosterone) were compared as CYP3A probe substrates. The results show that the evaluation for MBI does not depend on the probe substrates used in the assay. In addition, we established an automated assay to distinguish quasi-irreversible and irreversible binding to CYP3A in which the quasi-irreversible inhibitors such as diltiazem, verapamil, and nicardipine were dissociated from CYP3A by the addition of potassium ferricyanide, whereas the irreversible inhibitors such as clozapine, delavirdine, and mibefradil were not. It provides useful information related to chemical structures likely to cause MBI. By using these MBI assays supported by an extensive database of marketed compounds, a systematic MBI evaluation paradigm was established and has been incorporated into our drug discovery process.The cytochrome P450 (P450) superfamily comprises many isozymes that metabolize xenobiotic chemicals, including drugs (Guengerich, 2001). CYP1A2, 2C9, 2C19, 2D6, and 3A participate in the metabolism of approximately 80% of therapeutic drugs, such that the majority of P450-mediated drug metabolism is mediated by the CYP3A family (Wienkers and Heath, 2005). CYP3A4 is a major isoform of CYP3A. It has been reported that CYP3A5 may also contribute to the metabolism of CYP3A4 substrates because of the overlapping substrate specificity with CYP3A4 . Drugs metabolized by P450s may also inhibit the metabolism of coadministered drugs, which results in an increased blood concentration of the coadministered drugs (Bertz and Granneman, 1997). As a result, a patient to whom two or more drugs are administered might suffer from adverse effects induced by such a drug-drug interaction (DDI). Drugs such as terfenadine, mibefradil, cisapride, and nefazodone have been withdrawn from the market because of P450-related DDIs (Wienkers and Heath, 2005). Consequently, pharmaceutical companies now investigate the P450 inhibitory potential of drug candidates in the early stage of development (Wienkers and Heath, 2005). P450 inhibition can be classified into three categories: reversible, quasi-irreversible, and irreversible inhibition (Murray, 1997;Lin and Lu,...

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Section: Discussionmentioning

confidence: 99%

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Watanabe

Nakamura²,

Okudaira³

et al. 2007

Drug Metabolism and Disposition

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“…The extent of EE2-dependent SHBG induction is influenced by the dose of EE2 and the duration of use. Daily oral administrations of 60 Ixg EE2 maximally, increase SHBG levels by 300% [10] within 10 days. Coadministered progestins have different effects on the SHBG induction by daily EE2 doses of 30-35 Ixg.…”

Section: Introductionmentioning

confidence: 96%

“…More recent investigations have demonstrated an absolute oral bioavailability of 60% and a metabolic clearance of 5-7 ml min -1 kg -l. Various progestins have been shown not to influence EE2 pharmacokinetics [7][8][9][10]. EE2 induces the hepatic synthesis of SHBG but is, itself, not bound to this protein.…”

Section: Introductionmentioning

confidence: 98%

A single-dose and 3-month clinical—pharmacokinetic study with a new combination oral contraceptive

Heuner¹,

Kuhnz²,

Heger-Mahn³

et al. 1995

Adv Contracept

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The study was performed in 14 young women. The combination oral contraceptive contained 75 microgram gestodene (GSD) and 20 microgram ethinyl estradiol (EE2) per dosage unit. The volunteers received a single dose on day 21 of a treatment-free precycle (PCd21) and, after a washout period of 7 days, used the preparation in a 21 d/7 d schedule for three months. Daily drug serum level profiles were taken on PCd21 and on days 1 and 21 of treatment cycles 1 and 3. In addition, trough drug serum levels were followed every other day during treatment cycles 1 and 3. Serum levels of GSD, EE2, CBG, SHBG and testosterone (T) were determined by means of specifically developed or commercially available RIAs. Pharmacokinetic evaluation was carried out with TOPFIT and parameters were evaluated for differences with the t-test. Main target variables were Cmax, tmax and AUC for EE2, GSD and unbound GSD on day 21, cycle 3 vs. PCd21. EE2 pharmacokinetics were in agreement with a dose of 20 microgram/unit. Single-dose Cmax of 65 pg/ml and AUC of 612 pg h ml(-1) increased by 40-60% during treatment cycles as a result of accumulation EE2 induced basal SHBG (102nmol/L) and CBG (42 microgram/ml) serum levels to about 220 nmol/L and 87 microgram/ml, respectively, at the end of treatment cycles 1 and 3. Serum T levels dropped to 50% of baseline levels during treatment cycles and free T concentrations were reduced by 60-70%. GSD pharmacokinetics at the end of treatment cycles 1 and 3 were different from single-dose pharmacokinetics. Single-dose Cmax of 3.5 ng/ml and AUC 0-24 h of 22 ng h ml(-1) increased to steady-state levels of 8-8.7 ng/ml and 90-106 ng h ml(-1), respectively. The increase in GSD levels under treatment is the result of two parallel processes, i.e. accumulation and enlargement of the specific binding compartment. This was shown by protein-binding experiments, demonstrating an increase in specific (SHBG) binding from 69% to 80% and a reduction in the free fraction of GSD by 40% during treatment. The results of GSD and EE2 pharmacokinetics obtained in the present study confirm previous results with Femodene, when the reduction in the EE2 dose by 10 microgram/d is taken into account.

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“…clearance of 16.47 L/h via the well‐stirred liver model, using the retrograde calculator within the Simcyp simulator after subtracting renal clearance. Based on the study carried out by Reed et al ., the percentage of unchanged drug excreted in the urine is reported as 6% of an oral dose; hence a value of ∼2.1 L/h was estimated for renal clearance from a mean oral clearance of 34.6 L/h …”

Section: Resultsmentioning

confidence: 99%

“…Based on the study carried out by Reed et al, 8 the percentage of unchanged drug excreted in the urine is reported as 6% of an oral dose 5 ; hence a value of 2.1 L/h was estimated for renal clearance from a mean oral clearance of 34.6 L/h. 20,21 A combination of bottom-up (using scaled-up in vitro data) and top-down (using clinical data) approaches was used to assign the contributions of the respective enzymes to the systemic clearance of EE and hence obtain estimates of fm. Assignment of the scaledup hepatic metabolic CL int of 66.77 ll/min/mg protein due to 2hydroxylation (which constitutes greater than 90% of the hydroxylated metabolites) of EE from the in vitro study carried out by Shiraga et al in human liver microsomes (HLM), 22 resulted in a contribution of 0.2 to the overall systemic clearance of EE (fm CYP ).…”

Section: Relative Contributions Of Metabolic Routes In the Livermentioning

confidence: 99%

Risk–Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach

Ezuruike

Humphries

Dickins

et al. 2018

Clin Pharma and Therapeutics

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Current formulations of combined oral contraceptives (COC) containing ethinylestradiol (EE) have ≤35 μg due to increased risks of cardiovascular diseases (CVD) with higher doses of EE. Low‐dose formulations however, have resulted in increased incidences of breakthrough bleeding and contraceptive failure, particularly when coadministered with inducers of cytochrome P450 enzymes (CYP). The developed physiologically based pharmacokinetic model quantitatively predicted the effect of CYP3A4 inhibition and induction on the pharmacokinetics of EE. The predicted Cmax and AUC ratios when coadministered with voriconazole, fluconazole, rifampicin, and carbamazepine were within 1.25 of the observed data. Based on published clinical data, an AUCss value of 1,000 pg/ml.h was selected as the threshold for breakthrough bleeding. Prospective application of the model in simulations of different doses of EE (20 μg, 35 μg, and 50 μg) identified percentages of the population at risk of breakthrough bleeding alone and with varying degrees of CYP modulation.

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Influence of repeated oral doses of ethinyloestradiol on the metabolic disposition of [ 13 C 2 ]-ethinyloestradiol in young women

Abstract: Since the clearance in particular remained unchanged after repeated oral administration of ethinyloetradiol, the hypothesis that ethinyloestradiol can inhibit its own metabolism in vivo can be rejected.

Cited by 10 publications

References 8 publications

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

A single-dose and 3-month clinical—pharmacokinetic study with a new combination oral contraceptive

Risk–Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach

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