Eileen Smith

The effect of rifampicin oh the pharmacokinetics of ethynylestradiol in women

A single dose of Minovlar (50 microgram ethynylestradiol (EE) and 1 mg norethindrone acetate) was given to seven women during treatment with rifampicin (450-600 mg/day) and again one month after stopping rifampicin. Blood samples were taken at intervals over a 24-hour period. The area under the plasma EE versus time curve increased significantly on stopping rifampicin from 1014 +/- 317 pg/ml x h (mean +/- SE) to 1747 +/- 218 pg/ml x h (p less than 0.01). The terminal plasma half-life increased from 2.9 +/- 0.8 h to 6.3 +/- 1.4 h (p less than 0.005). The sex hormone binding globulin (S.H.B.G.) capacity was also reduced from 213.4 +/- 11.5 nmoles to 129.0 +/- 7.7 nmoles/1 after stopping rifampicin. In one patient starting rifampicin who was taking Minovlar as a long-term oral contraceptive, a fall in the plasma EE concentration was associated with a rise in the plasma follicle stimulating hormone concentration. These effects of rifampicin on EE pharmacokinetics are consistent with induction of the microsomal enzymes that metabolise EE.

The Effect of Rifampicin on Norethisterone Pharmacokinetics

SummaryThe pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450–600 mg/day). Rifampicin caused a significant reduction in the A. U. C. of a single dose of 1 mg norethisterone from 37.8±13.1 to 21.9±5.9 ng/ml X h (p<0.01). The plasma norethisterone half life (β-phase) was also reduced from 6.2±1.7 to 3.2±1.0 h (p<0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/ml. Rifampicin caused a significant increase in antipyrine clearance, 6β-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there were no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A. U. C. during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin.

Kinetics of norethindrone in women. II. Single-dose kinetics.

In order to study the kinetics of norethindrone in women, we have administered single doses of 4 preparations of norethindrone (N) to 6 women (aged 21 to 23) in random order. The preparations were 1 mg N acetate and 50 µg ethinylestradiol EE2) (Minovlar), a dose of 1.05 mg N (Noriday), 3 mg N acetate and 50 µg EE2 (Gynovlar), and an intravenous preparation of 1 mg N with 50 µg EE2. Blood samples were taken at intervals up to 24 hr after dosing and plasma norethindrone concentrations were measured by radioimmunoassay. The plasma concentration decay slope fitted a two‐component open model with an initial rapid decay (half life 0.41 to 2.6 hr) followed by a slower beta phase with a half‐life of between 4.8 and 12.8 hr. The kinetics of norethindrone were not affected by the concomitant administration of EE2. The bioavailability of norethindrone after an oral dose of 1 mg was between 47% and 73% compared with an equivalent intravenous dose. The plasma clearance of norethindrone after 1 mg N acetate and 50 µg EE2 was 404.7 ± 31.7 ml/kg/hr and the apparent volume of distribution was 4.28 ± 0.56 L/kg. These values were not significantly different from the figures obtained after administration of 1.05 mg N. After an oral dose of 3 mg N acetate and 50 µg EE2, the bioavailability of norethindrone was significantly less (between 32% and 70%) than that after 1 mg N acetate and 50 µg EE2 explaining, at least in part, the lower than expected plasma concentrations of norethindrone in women on long‐term treatment with 3 mg N acetate and 50 µg EE2.

The effect of antibiotics on the enterohepatic circulation of ethinylestradiol and norethisterone in the rat.

Abstract Seventy-one percent of a given dose of [ 3 H]-ethinylestradiol ([ 3 H]-EE 2 ) and 76.0% of a given dose of [ 3 H]-norethisterone ([ 3 H]-N) were excreted in the bile of female rats in 4 h. The majority of radio-activity appeared in the glucuronide fraction. Characterization of the hydrolysed glucuronide fraction obtained after administration of [ 3 H]-EE 2 gave evidence that approximately 10.0% of the administered dose may be directly conjugated to form ethinylestradiol glucuronide. In contrast, there was no evidence of direct conjugation of norethisterone. In a linked rat preparation 15.4% of the given dose of [ 3 H]-EE 2 was excreted in the bile of control recipient rats in 7 h; this was reduced to 5.2% in neomycin pretreated and 6.0% in ampicillin pretreated animals. With [ 3 H]-N, 13.2% of the dose was excreted in the bile of control recipient rats in 7 hours and this was reduced to 3.6% in neomycin pretreated and 3.9% in ampicillin pretreated animals. These results show that antibiotic treatment reduces the enterohepatic circulation of synthetic steroids in the rat.

Kinetics of norethindrone in women; I. Radioimmunoassay and concentrations during multiple dosing

A radioimmunoassay for norethindrone has been developed with the use of an antiserum raised in rabbits after the injection of norethindrone‐3‐carboxymethyloxime linked to bovine serum albumin. The immunoassay is sensitive to 30 pg/ml norethindrone. With this assay plasma concentrations of norethindrone in 40 women receiving 1 mg norethindrone acetate with 50 µg ethinylestradiol were between 1.6 and 15.2 ng/ml 12 hr after dosing during multiple dosing. After a single dose of 1 mg of norethindrone acetate with 50 mg ethinylestradiol, the plasma half life (t½) of the terminal apparently monoexponential phase of norethindrone decay was between 6.1 and 12.3 hr in 6 patients. During long‐term therapy with contraceptive steroids the plasma t½ of norethindrone did not differ from the t½ after a single dose. In 4 women receiving contraceptive steroids for the first time. plasma concentrations of norethindrone rose progressively during the first cycle to concentrations higher than predicted from simple accumulation pharmacokinetics. The sex hormone‐binding globulin capacity also increased and there was a good correlation between the plasma concentration of norethindrone and the sex hormone‐binding capacity (r between 0.695 and 0.910 in 4 patients). In 3 women starting the contraceptive steroid 4 wk postpartum there was a reduction of plasma norethindrone concentration with time (r = 0.528 p < 0.01) and this correlated with a fall in the sex hormone‐binding capacity (p < 0.05). In women taking a preparation containing 3 mg norethindrone acetate. the mean plasma norethindrone concentration was only 1.4 times as high as that in women taking 1 mg norethindrone acetate.

Ethynylestradiol and norethindrone metabolism by everted sacs of rat ileum

Abstract The absorption of radioactively labelled norethindrone and ethynylestradiol through the walls of everted sacs of rat ileum has been studied. Norethindrone was metabolised, probably by reduction of the A-ring, but there was little evidence of conjugation. The capacity of the norethindrone metabolising system was high enough to be of pharmacological significance. There was no evidence of metabolism of the steroid nucleus in the case of ethynylestradiol, but there was extensive conjugation as a glucuronide, particularly by middle portions of the ileunu.

Biliary excretion of synthetic sex steroids in heterozygous and homozygous gunn rats

Abstract 87.9% of a given dose of [ 3 H]Norethisterone ([ 3 H]N) and 76.7% of [ 3 H]Ethinyloestradiol ([ 3 H]EE 2 ) were excreted in the bile of male heterozygous Gunn rats in 2 hours Similarly, 86.9% of a given dose [ 3 H]N and 84.0% of [ 3 H]EE 2 were excreted in the bile of male homozygous Gunn rats in 2 hours. In both heterozygous and homozygous rats glucuronide conjugates were present. Despite the lesion in UDP-glucuronyltransferase, the homozygous rats is able to conjugate the synthetic steroids apparently normally.

An investigation of the effects of phenobarbitone on the pharmacokinetics of norethindrone in the rat using liver perfusion and everted gut sacs

Previous in vivo studies have suggested that phenobarbitone increases the first pass clearance of norethindrone in the rat by induction of enzymes both in the gut wall and liver. In the present study phenobarbitone caused an increase in both the production of highly polar ether-extractable metabolites and the conjugation of the steroid as it crossed the wall of the everted gut sac preparation. In addition, there was a marked increase in the uptake of norethindrone into the liver followed by increased phase I metabolism in the isolated perfused liver. As expected for a highly cleared drug, enzyme induction had no measurable effect on the terminal half-life of norethindrone in the perfused liver preparation.

The pharmacokinetics of tritiated ethinylestradiol in the rabbit

The disappearance of ethinylestradiol from the blood of rabbits has been studied, following the intravenous administration of this steroid. The disappearance followed two exponentials, the first having a half life (t1/2) of 5.5 min and the second, apparently terminal exponential was also rapid (t1/2-69 min). The plasma clearance was 150 ml/min which suggests almost total clearance of this steroid during a single passage through the liver. Bile contained a significant concentration of EE conjugates and thus this steroid could undergo enterophepatic recirculations. A large oral dose of unlabelled EE, given prior to intravenous administration of tritiated EE, considerably altered the pharmacokinetics of the latter by saturating both phase one metabolism (changes of the steroid nucleus) and the secretion of conjugates into bile. It was not clear whether phase two metabolism (conjugation) was also saturated.