An investigation of the pharmacokinetics of ethynylestsadiol in women using badioimmunoassay

Back, DJ; Breckenridge, AM; Crawford, Francesca E.; MacIver, M Bruce; Orme, M.; Rowe, Philip H.; Watts, M.J.

doi:10.1016/0010-7824(79)90098-2

Cited by 126 publications

(37 citation statements)

References 11 publications

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“…For example, plasma levels of EE2-Sul are approximately 23 times greater than those of EE2 after a large (3 mg) oral dose of EE2 (Back et al, 1980). At regular doses of EE2 (ϳ50 g), EE2 plasma levels range between 0.25 and 0.71 nM (Nilsson and Nygren, 1978;Back et al, 1979;Akpoviroro and Fotherby, 1980;Brenner et al, 1980). If one assumes that the EE2 to EE2-Sul ratio is independent of dose, then EE2-Sul plasma levels are estimated to be within the range of 5.6 to 15.9 nM.…”

Section: Discussionmentioning

confidence: 99%

“…Also of note is the high first-pass 3-Osulfation (gut Ͼ liver), which likely limits the oral bioavailability of EE2 (20 -65%) (Orme et al, 1989). After oral administration of EE2, EE2 and its metabolites are excreted into bile (ϳ35% of the dose) and can undergo enterohepatic recirculation (Back et al, 1979;Maggs et al, 1983). Because of extensive sulfation, the 3-O-sulfate conjugate of EE2 (EE2-Sul) circulates in human plasma at higher concentrations (Ͼ20-fold) than parent EE2 and its 3-O-glucuronide (Akpoviroro and Fotherby, 1980;Back et al, 1980).…”

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confidence: 99%

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Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver Drug Transporters

Han¹,

Busler²,

Yang³

et al. 2010

Drug Metab Dispos

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ABSTRACT:17␣-Ethinylestradiol (EE2), a component of oral contraceptives, is known to undergo considerable first-pass 3-O-sulfation in the intestine and liver. Once formed, the 3-O-sulfate conjugate (EE2-Sul) is detected in circulation at appreciable levels (versus parent EE2) and is present in bile. Therefore, hepatic uptake of EE2-Sul was assessed with suspensions of cryopreserved human primary hepatocytes. In this instance, there was evidence for active (temperature-dependent) uptake, which was described by a two-K m (Michaelis constant) model (K m1 ‫؍‬ 220 nM; K m2 ‫؍‬ 15.5 M). Uptake was inhibited (ϳ90%) by bromosulfophthalein but not by tetraethylammonium or p-aminohippurate. In agreement, EE2-Sul was shown to be a substrate of recombinant organic anion transporter peptides (OATP1B1 and OATP2B1), and Na ؉ /taurocholate-cotransporting polypeptide (NTCP), expressed individually in human embryonic kidney (HEK) 293 cells. Transport by OATP1B1 was described by two K m values (87 nM and 141 M), whereas OATP2B1-and NTCP-mediated uptake into HEK-293 cells conformed to single K m kinetics (10.7 and 2.6 M, respectively). EE2-Sul was also assessed as an efflux transporter substrate using membrane vesicles expressing bile salt export pump, breast cancer resistance protein (BCRP), and individual forms of multidrug resistance-associated protein (MRP1, MRP2, and MRP3). Transport studies were also conducted with a cell line expression Pglycoprotein. Only vesicles that contained BCRP exhibited ATPdependent uptake of EE2-Sul (K m1 ‫؍‬ 2.9 and K m2 ‫؍‬ 307 M). Collectively, the data show that hepatic uptake of EE2-Sul can be mediated by three transporters (OATP1B1, OATP2B1, and NTCP), whereas biliary excretion of EE2-Sul into bile likely involves BCRP.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver Drug Transporters

Han¹,

Busler²,

Yang³

et al. 2010

Drug Metab Dispos

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“…in the United Kingdom. Ethinyloestradiol is well absorbed from the gastrointestinal tract but some 60% of the drug is metabolised by the first pass metabolism during absorption into the body (Back et al, 1979b). The metabolites that are produced both by the gut wall and by the liver include sulphate and glucuronide conjugates which are then excreted in the bile.…”

Section: Discussionmentioning

confidence: 99%

“…Once the bile reaches the intestine, the conjugates may be broken down to liberate unchanged ethinyloestradiol which is then reabsorbed. The plasma concentration profile of ethinyloestradiol is in keeping with a considerable enterohepatic circulation (Back et al, 1979b). It is known that gut bacteria possess enzymes that can hydrolyse glucuronide conjugates (Hawksworth et al, 1971) but it is not clear how much sulphatase activity these bacteria possess.…”

Section: Discussionmentioning

confidence: 99%

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The effects of ampicillin oral contraceptive steroids in women.

Back¹,

Breckenridge²,

MacIver³

et al. 1982

Brit J Clinical Pharma

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1 Thirteen women taking long term oral contraceptive steroids were studied while taking ampicillin (500 mg three times daily) and compared to a control cycle while not taking ampicillin.2 There were no significant changes in the plasma concentrations of ethinyloestradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyloestradiol were noted in two women.3 We conclude that most patients taking oral contraceptive steroids do not need to take alternative contraceptive precautions while taking ampicillin.

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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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An investigation of the pharmacokinetics of ethynylestsadiol in women using badioimmunoassay

Cited by 126 publications

References 11 publications

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver Drug Transporters

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver Drug Transporters

The effects of ampicillin oral contraceptive steroids in women.

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

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