S.F.M. Grimmer

The biliary and urinary metabolites of [3H]17α-ethynylestradiol in women

1. The metabolism of 17α-ethynyl[6,7-3H]estradiol (3H-EE2) (50 μg) given orally was studied in two groups of women: (a) six subjects from whom duodenal bile samples were obtained after 4h by endoscopic aspiration; (b) two subjects with bile-duct (T-tube) drainage.2. The first group eliminated 16.6 ± 7.8% (mean ± S.D.) of the dose in urine over 72 h, the second group 28.6% and 27.5%. Biliary excretion by the latter was 41.9% and 28.3% of the dose, respectively, during the first 24 h after dosing.3. The metabolites excreted in bile and urine were largely polar conjugates: 1–12% of the 3H was ether extractable. Approx. 70–90% of urinary and biliary 3H was extractable following β-glucuronidase-arylsulphohydrolase hydrolysis. Both β-glucuronidase and arylsulphates were excreted.4. Unchanged 3H-EE2 was the principal 3H-labelled component of the glucuronide and arylsulphate fractions of bile, and it was a major component of urinary fractions. 2-Hydroxy-EE2 and 2-methoxy-EE2 were identified as conjugated biliary ...

Plasma concentrations of 3-keto-desogestrel after oral administration of desogestrel and intravenous administration of 3-keto-desogestrel.

The plasma concentrations of 3-keto-desogestrel have been measured by radioimmunoassay in a crossover study in nine healthy female volunteers given oral desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms) and intravenous (i.v.) 3-keto-desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms). Bioavailability ranged between 40.0 and 113% with a mean value ( +/- SD) of 76.1 +/- 22.5%. Only 3 subjects had a bioavailability of less than 70%. There was no significant difference in the elimination half life of 3-keto-desogestrel which was 12.6 +/- 4.1h following i.v. administration and 11.9 +/- 4.1h after oral administration of desogestrel.

The bioavailability of ethinyloestradiol and levonorgestrel in patients with an ileostomy

The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostomy following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 +/- 10.9% (+/- S.D.) compared to a control value of 45.0 +/- 6.1% (p greater than or equal to 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 +/- 13.1% compared to 104.6 +/- 22.3% in the controls (p greater than or equal to 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.

Comparative pharmacokinetics of levonqrgestrel and ethinyloestradiol following intravenous, oral and vaginal administration

The plasma concentrations of levonorgestrel (LNG) and ethinyloestradiol (EE2) have been measured in a random crossover study in five healthy female volunteers given a combination oral contraceptive tablet (250 micrograms LNG and 50 micrograms EE2) by the oral route and per vaginum and also receiving the same dose intravenously. The fractional bioavailability of LNG after oral administration was 1.00 +/- 0.16 (mean +/- S.D.) and after vaginal insertion 0.88 +/- 0.16. The time to peak (tmax) was significantly longer and the peak concentration (Cmax) significantly reduced following vaginal administration. The fractional bioavailability of EE2 after oral dosing was 0.62 +/- 0.11 and after vaginal insertion 0.74 +/- 0.16; tmax was prolonged, hence absorption was slower from the vagina. The reduced rate of absorption was evident in the differences seen in the area under the curve for early time periods for both steroids. However, overall bioavailability is not reduced for either steroid when a single tablet is inserted into the vagina.

The effect of cotrimoxazole on oral contraceptive steroids in women

Nine women taking long-term oral contraceptive steroids (Trinordiol) were studied during a cycle while taking cotrimoxazole (1 gm twice daily) and the results were compared to the previous control cycle. During the cotrimoxazole cycle, there was a significant increase in the plasma concentration of ethynylestradiol (EE). In plasma samples taken on 4 successive days 10-12 hours after dosing, the plasma EE concentration rose from 29.3 +/- 5.0 pg/ml to 38.2 +/- 5.8 pg/ml (mean +/- S.E. P less than or equal to 0.02). In samples taken 24 hours after dosing, the increase was from 18.9 +/- 2.5 pg/ml to 27.8 +/- 4.0 pg/ml (P less than or equal to 0.05). Plasma F.S.H. values in these latter samples, decreased from 4.8 +/- 0.6 mIu/ml to 3.4 +/- 0.5 mIu/ml (P less than or equal to 0.01). No significant changes were noted in the plasma concentrations of levonorgestrel or progesterone. The rise in plasma concentration of EE during cotrimoxazole therapy is attributed to an inhibition of the metabolism of EE by cotrimoxazole as has been shown with other drugs. Short courses of cotrimoxazole are unlikely to cause any adverse effects on contraceptive control when given to women taking long-term oral contraceptive steroids.

Pharmacokinetics of oral contraceptive steroids following the administration of the antimalarial drugs primaquine and chloroquine

The effects of a single dose of two antimalarial drugs chloroquine (CQ) and primaquine (PQ) on the pharmacokinetics of a combined oral contraceptive (O.C.) have been studied in volunteers. Each woman was studied on 3 separate occasions over 3 cycles and plasma concentrations of ethinyloestradiol (EE2) and levonorgestrel were measured by radioimmunoassay following administration of a single dose of O.C. (30 micrograms EE2 + 150 micrograms levonorgestrel) in the absence and presence of the antimalarial drugs (PQ, 45 mg; CQ, 300 mg). Neither CQ or PQ given 1 h before the O.C. had any significant effect on plasma concentrations of EE2 or levonorgestrel or on any pharmacokinetic parameter determined. There is therefore, no evidence that CQ or PQ interfere with the hepatic handling of O.C.s. This is in contrast to previously reported inhibitory effects of PQ on the metabolism of antipyrine.

The in‐vitro mucosal conjugation of ethinyloestradiol and the bioavailability of oral contraceptive steroids in patients with treated and untreated coeliac disease

The ethinyloestradiol (EO2) component of oral contraceptive steroids is extensively conjugated with sulphate by the gut wall. The ability of gastrointestinal mucosa to conjugate EO2 has been examined in vitro in samples of mucosa taken from normal women as well as from women with coeliac disease. The percentage conjugation per mg dry weight for normal tissue (n= 11) was 17.1 ± 6.4 (mean ± s.d.) while in untreated coeliac tissue (n= 6) the figure was 6.3 ± 3.6% (P < 0.01). In tissue from patients with treated coeliac disease (n= 5) the figure was 12.1 ± 3.2%.

Urinary concentrations of steroid glucuronides in women taking oral contraceptives

The aim of this study was to use measurements of urinary steroid glucuronides to confirm the suppression of ovulation of ovulation in women taking oral contraceptives. Urinary concentrations of oestrone-3-glucuronide (E1G) and pregnanediol-3 alpha-glucuronide (Pd-3-G) were measured by radioimmunoassay in early morning urine samples from six normally-menstruating women and six women who were taking combined oral contraceptives. In the normally-menstruating women, E1G concentrations, and the E1G/Pd-3-G ratio, increased 2-3 fold before ovulation. There was no midcycle increase in either measure in women taking oral contraceptives. We suggest that measurement of these steroid metabolites provides a means of assessing the anti-ovulatory effects of oral contraceptives.