The gut wall metabolism of ethinyloestradiol and its contribution to the pre‐systemic metabolism of ethinyloestradiol in humans.

Back, DJ; Breckenridge, AM; MacIver, M Bruce; Orme, M.; Purba, HS; Rowe, Philip H.; Taylor, I. W.

doi:10.1111/j.1365-2125.1982.tb01382.x

Cited by 71 publications

(48 citation statements)

References 10 publications

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“…4) nor in the presence of GSH (data not shown). Because EE undergoes extensive gut (E g ϭ 44%) and liver (E h ϭ 25%) first-pass metabolism in humans (Back et al, 1982), MRP2 and MRP3 may be the physiolog- 3 H]EE-G for 5 min in the presence of 5 mM ATP or AMP and an ATP-regenerating system in transport buffer. Before the incubation of the vesicles, EE-S was added at concentrations of 0, 2, 5, 20, 50, and 100 M, respectively, and preincubated with the ligand, ATP, or AMP and the ATP-regenerating system at 37°C for 3 min.…”

Section: Discussionmentioning

confidence: 99%

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Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

Chu¹,

Huskey²,

Braun³

et al. 2004

J Pharmacol Exp Ther

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Ethinylestradiol (EE) is one of the key constituents of oral contraceptives. Major metabolites of EE in humans are the glucuronide and sulfate conjugates, EE-3-O-glucuronide (EE-G) and EE-3-O-sulfate (EE-S). In the present study, transport of EE-G and EE-S by the human multidrug resistance proteins MRP1, MRP2, and MRP3 was investigated using inside-out membrane vesicles, isolated from Sf9 cells expressing human MRP1, MRP2, or MRP3. Vesicular uptake studies showed that EE-G was not a substrate for MRP1, whereas an ATP-dependent and saturable transport of [ 3 H]EE-G was observed in MRP2 (K m of 35.1 Ϯ 3.5 M) and MRP3 (K m of 9.2 Ϯ 2.3 M) containing vesicles. EE-S was not transported by either MRP1, MRP2, or MRP3. However, low concentrations of EE-S stimulated MRP2-mediated uptake of ethacrynic acid glutathione.EE-S also stimulated MRP2 and MRP3-mediated uptake of 17␤-estradiol-17␤-D-glucuronide. Interestingly, EE-S stimulated strongly MRP2-and MRP3-mediated uptake of EE-G by increasing its apparent transport affinity, whereas no reciprocal stimulation of EE-S uptake by EE-G was observed. These data indicate that EE-S allosterically stimulates MRP2-and MRP3-mediated transport of EE-G and is not cotransported with EE-G. Our studies demonstrate specific active transport of a pharmacologically relevant drug conjugate by human MRP2 and MRP3, involving complex interactions with other organic anions. We also suggest that caution needs to be taken when using only competition studies as screening tools to identify substrates or inhibitors of MRP-mediated transport.17␣-Ethinyl estradiol (EE), a synthetic estrogen, is an essential constituent of oral contraceptives, which have been widely prescribed since the 1970s. Over 60 million women currently take oral contraceptives, and their safety profile is well established. Numerous examples are known (Stockley, 1999) where coadministration of EE with a range of other drugs can result in decreased plasma levels of EE with the commensurate failure of contraception and breakthrough bleedings. Alterations in EE metabolism and disposition are proposed to occur via induction of hepatic or gut enzymes involved in the metabolism and/or transport of EE and its metabolites.

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Section: Discussionmentioning

confidence: 99%

“…The pharmacokinetics and metabolism of EE in humans occurs both in gut and liver, respectively, where the mean bioavailability is reported to be 45% (Back et al, 1982;Rogers et al, 1987). EE mainly undergoes sulfation and glucuronidation, resulting in the formation of EE-3-O-sulfate (EE-S) and EE-3-O-glucuronide (EE-G).…”

mentioning

confidence: 99%

Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

Chu¹,

Huskey²,

Braun³

et al. 2004

J Pharmacol Exp Ther

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“…These techniques have been discussed in a recent review . It has been previously demonstrated in studies with ethinyloestradiol that the overall nature and extent of metabolite production in the Ussing Chamber set-up closely parallels what happens in situ Back et al, 1982). Since metabolites appear preferentially on the mucosal side in the Ussing Chamber (possibly because the muscularis mucosa acts as a barrier to drug gaining ready access to the serosal side), we have concentrated our attention on determining the metabolite profile in mucosal fluid.…”

Section: Discussionmentioning

confidence: 97%

Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa.

Madden

Back

et al. 1989

Brit J Clinical Pharma

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1 The intestinal mucosal metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using the Ussing chamber technique. Histologically normal ileum or colon was obtained from eight patients undergoing various resections. The mucosal sheets were mounted between two perspex chambers. 2 Two hours after addition of [3H]-Dg (0.2pXCi; 100 ng) to the mucosal chamber, more than 90% of the steroid was present in that chamber. In studies with colon, metabolite analysis showed that 55.4 ± 11.7% (mean ± s.d.; n = 6) of drug present was Dg, 28.9 + 11.4% as unconjugated Phase I metabolites, 13.3 ± 2.6% as sulphate conjugates and 2.5 + 1.5% as glucuronide conjugates. 3 By co-chromatography with authentic metabolites and mass spectrometry, it was shown that 3-keto desogestrel is formed in the mucosa. This is the active metabolite of desogestrel. A large peak of radioactivity did not co-chromatograph with any known metabolites and has been tentatively identified as ring hydroxylated products of 3-keto desogestrel. 4 The effect of the synthetic oestrogen ethinyloestradiol (EE2) on the metabolite profile of Dg was studied. In the presence of increasing concentrations of EE2 (100 ng, 1 and 10 ,ug), there was competition for sulphation such that the sulphate fraction decreased by 32, 49 and 48% respectively. 5 The results of this study indicate substantial first pass metabolism of desogestrel by the gut mucosa with evidence for the formation of the active metabolite. The extent of phase I metabolism is unusual.

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“…The small intestine has the ability to metabolize drugs by numerous pathways involving both phase 1 and phase 2 reactions [39]. The gut wall metabolism is an important factor in the low systemic bioavailability of EE when it is orally administered [40]. 2.…”

Section: Discussionmentioning

confidence: 99%

Effect of glucomannan and the dosage form on ethinylestradiol oral absorption in rabbits

González¹,

Fernández²,

Sahagún³

et al. 2004

Contraception

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To the beneficial properties of dietary fiber in human health, several disadvantages can be added as the possible modification of the bioavailability of other drugs when administered by the oral route. In this study, the influence of glucomannan in the oral bioavailability of ethinyl estradiol (EE), when administered to female rabbits in two different dosage forms (enteric capsules and dispersed in water), was established. To carry out the study, three groups of six animals each were used. All animals received 1 mg kg À1 oral EE, and rabbits in groups 2 and 3 received 1.5 g glucomannan dispersed in water or in enteric capsules, respectively, immediately before EE. When comparing the results obtained after the administration of EE/glucomannan dispersed in water with those obtained after the administration of this estrogen without fiber, we can see that C max is 1.4 times lower, AUC 1.9 times lower and that t max is identical (10 min). However, after the administration of fiber in enteric capsules, AUC and C max are higher (4.1 and 7.8 times, respectively) than when the estrogen was administered alone, and also, there is a delay in t max (20 min). After the administration of glucomannan in the enteric capsule, the fiber forms, as in the stomach, a highly viscous solution in the gut that would limit EE access to the mucosal surface delaying its absorption. However, this effect could be compensated by a reduction of EE metabolism in the intestinal wall, leading to a higher absorption of the estrogen. D 2004 Elsevier Inc. All rights reserved.

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The gut wall metabolism of ethinyloestradiol and its contribution to the pre‐systemic metabolism of ethinyloestradiol in humans.

Cited by 71 publications

References 10 publications

Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa.

Effect of glucomannan and the dosage form on ethinylestradiol oral absorption in rabbits

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