Bio-availability and pharmacokinetics of cyproterone acetate-14C and ethinyloestradiol-3H after oral administration as a coated tablet (SH B 209 AB)

Speck, Ulrich; Wendt, H.; Schulze, P.; D, Jentsch

doi:10.1016/0010-7824(76)90083-4

Cited by 51 publications

(17 citation statements)

References 4 publications

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“…The changes in the pharmacokinetic parameters of EE after its administration with glucomannan dispersed in water could be explained, in agreement with Fernandez et al [15] and Garcia et al [16], as follows: in the stomach, where this drug is well absorbed [32,33], the fiber forms a highly viscous solution, trapping EE inside it, and therefore, resulting in decreased drug absorption and lower values for C max . This phenomenon will also take place in the upper portions of the intestine, where glucomannan forms a gel that prevents drug access to mucosal surfaces, resulting in a lower AUC.…”

Section: Discussionsupporting

confidence: 84%

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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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Section: Discussionsupporting

confidence: 84%

“…This drug is mainly absorbed in the stomach [33]. When EE reaches the intestine, it is widely metabolized, being that the gut wall metabolism is an important factor in the low systemic bioavailability of this estrogen [34,35].…”

Section: Introductionmentioning

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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“…Moreover, as highly lipophilic compounds, progestins have a large volume of distribution, indicating that their tissue concentration is considerably higher than the corresponding plasma concentrations. For instance, cyproterone acetate studies in rats and humans demonstrated up to 16-fold higher concentrations of this progestin in all organs investigated when compared to the plasma with the highest concentrations in the liver (Speck et al, 1976;Schleicher et al, 1998). Thus, it seems conceivable that tissue concentrations are high enough for MRP2 modulation.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Progestins With the Human Multidrug Resistance-Associated Protein 2 (Mrp2)

Lindenmaier

Becker²,

Haefeli³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Progestins are widely used as oral contraceptives and hormone replacement therapy. Recently it has been demonstrated that many progestins are inhibitors of P-glycoprotein, possibly explaining gender differences in drug actions. In vitro evidence suggested that at least norgestimate might also inhibit other transporters like the multidrug resistance-associated protein 2 (MRP2). We therefore investigated whether norgestimate, desogestrel, medroxyprogesterone acetate, norethisterone, progesterone, cyproterone acetate, chlormadinone acetate, and levonorgestrel inhibit MRP2 in vitro using confocal laser scanning microscopy and 5-chloromethylfluorescein diacetate as a prodrug of the fluorescent 5-chloromethylfluorescein (CMF), which is actively transported by MRP2 as glutathione conjugate. Of the progestins tested, only norgestimate (50 M) and progesterone (100 M) significantly increased intracellular CMF fluorescence by 62% and 53%, respectively. In conclusion, the progestins norgestimate and progesterone significantly inhibit the transport activity of MRP2 in vitro.Multidrug resistance-associated proteins (MRPs) are a subfamily of the ATP-binding cassette transport protein family involved in drug resistance (Schinkel and Jonker, 2003). MRP2 is a key member of this group and was identified in the canalicular membrane of hepatocytes as a transporter for organic anions extruding a wide range of glutathione, glucuronate, and sulfate conjugates into the bile (Ishikawa 1993;Ito et al., 1997;Paulusma and Oude Elferink, 1997). It was also detected in renal brush-border membranes, the intestine (Schaub et al., 1997), placenta (St.-Pierre et al., 2000;Gerk and Vore, 2002), and brain (Török et al., 2003). In human carcinoma, MRP2 may confer resistance to chemotherapy (Norris et al., 1996;Nies et al., 2001;Young et al., 2001;Schinkel and Jonker, 2003), and it appears also to play a role in drug-drug interactions (Fromm et al., 2000;Bramow et al., 2001;Bode et al., 2002;Huisman et al., 2002;Giessmann et al., 2004).In recent years it has been suggested that gender could alter the activity of drug transporters like P-glycoprotein (P-gp) (Cummins et al., 2002). Hence in a previous study we have investigated whether P-gp is inhibited by progestins used in oral contraceptives and hormone replacement therapy. All progestins tested had P-gp inhibitor properties, with some of them being as potent as the well known P-gp inhibitor quinidine (Fröhlich et al., 2004). Interestingly, one of the tested progestins (norgestimate) revealed an inhibitory effect on the transport of calcein-acetoxymethylester (calcein-AM) not only in the P-gp-overexpressing cell line L-MDR1, but also in the parental cell line LLC-PK1, which only expresses low amounts of P-gp (Decorti et al., 2001;Weiss et al., 2003;Fröhlich et al., 2004), indicating that this effect was not selective. Because LLC-PK1 expresses MRP2 (Evers et al., 1996;Decorti et al., 2001) and MRP2 can transport calcein-AM (Evers et al., 2000), these data may suggest that norgestimate also...

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“…14C-radioactivity in plasma, urine and feces was measured as described previously (3). Monitoring of PAA in plasma and urine was performed by HPLC chromatography and fluorimetric detection (4).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of pirazolac — A new anti-inflammatory drug — in human volunteers I. Absorption, disposition, biotransformation and excretion

Täuber¹,

Weiss²,

Krause³

et al. 1985

European Journal of Drug Metabolism and Pharmacokinetics

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The absorption, disposition, biotransformation and excretion of the nonsteroidal anti-inflammatory drug pirazolac were investigated in 6 volunteers (3 males, 3 females, age 50 greater than years) after intravenous and oral administration of 50 mg 14C-pirazolac as an aqueous solution of the sodium salt. Pirazolac was very rapidly and completely absorbed and bioavailable when orally administered in a dose of 50 mg in solution. Maximum pirazolac levels in plasma of 6 micrograms/ml (30% of dose in total plasma volume) were already reached after approx. 20 minutes. No metabolites were detectable in the plasma. Pirazolac was eliminated from the plasma in two phases with half-lives of 3 hours and 16 hours, respectively, regardless of administration route. After intravenous and oral administration approximately 80% of the dose was excreted with the urine and approximately 15% with the feces within 7 days, indicating a complete excretion of 14C-radioactivity. In urine, approximately 10% of the dose was identified as unchanged pirazolac and 70% as pirazolac ester glucuronide.

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Bio-availability and pharmacokinetics of cyproterone acetate-14C and ethinyloestradiol-3H after oral administration as a coated tablet (SH B 209 AB)

Cited by 51 publications

References 4 publications

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

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

Interaction of Progestins With the Human Multidrug Resistance-Associated Protein 2 (Mrp2)

Pharmacokinetics of pirazolac — A new anti-inflammatory drug — in human volunteers I. Absorption, disposition, biotransformation and excretion

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