M.L'e. Orme

An investigation of the pharmacokinetics of ethynylestsadiol in women using badioimmunoassay

Abstract A radioimmunoassay for ethynylestradiol (EE) which is applicable to plasma samples obtained from women, who have taken a combination type oral contraceptive, has been developed and fully validated. Plasma concentrations of EE rise to a peak of 128 pg/ml following the oral administration of 50 μg EE. Following the intravenous administration of the same dose of EE, plasma concentrations of the steroid declined biexponentially, the two half-lives being 0.83 and 6.75 hours. Comparison of the results of the intravenous and oral administration of the steroid suggested that its oral bioavailability is 42%. Although EE thus has a lower bioavailability than norethindrone, the pharmacokinetics of the two steroids, as reflected by half-lives, plasma clearance and volume of distribution, are very similar. The occurrence of a secondary peak in plasma at around 12 hours after dosing gave strong evidence that EE undergoes enterohepatic circulation in women; an event that may have considerable clinical significance.

The pharmacokinetics of levonorgestrel and ethynylestradiol in women: studies with Ovran and Ovranette.

A radioimmunoassay for levonorgestrel (Ng), which is applicable to plasma samples obtained from women who have taken a combination type oral contraceptive, has been developed and fully validated. Plasma concentrations of Ng rise to a peak of 3.6 ng/ml after an oral dose of 150 microgram and to 5.0 ng/ml after a 250 microgram dose. Following the intravenous administration of Ng, plasma concentrations of the steroid decline bi-exponentially with mean half-lives of 0.76 and 11.55 hours. Comparison of the results of the intravenous and oral administration of the steroid show a mean systemic bioavailability of 89% after the 150 microgram dose and 99% after a 250 microgram dose. This difference was not statistically significant. The values for volume of distribution were approximately half and the values for plasma clearance three times less than that previously reported for norethindrone. The plasma ethynylestradiol levels were also measured following administration of 30 microgram both intravenously and orally. The bioavailability and kinetics were similar to that previously reported for a 50 microgram dose. The peak values after oral dosing were 103 pg/ml and were reached by 1.0 hour in all subjects.

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.

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 lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids.

Patients taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine together with their oral contraceptive steroid may suffer contraceptive failure because of the enzyme-inducing properties of these anticonvulsants. We have examined, in six women, the effect of sodium valproate, an effective broad spectrum anticonvulsant, on the area under the plasma concentration versus time profile (AUC) of ethinyloestradiol (EE2) and levonorgestrel (Ng). Prior to sodium valproate therapy the mean AUC for EE2 was 880 +/- 109 pg/ml X h (+/- S.E.) and for levonorgestrel it was 29.1 +/- 2.9 ng/ml X h (n = 4). Between two and four months after sodium valproate therapy the mean AUC figures had not changed significantly, the figure for EE2 being 977 +/- 130 pg/ml X h and for levonorgestrel 29.2 +/- 1.9 ng/ml X h (p greater than or equal to 0.1 in each case). We conclude that sodium valproate in the dose used (200 mg b.d.) does not interact with oral contraceptive steroids.

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.

Dose‐dependent enzyme induction

Administration of qUinalbarbitone, 100 mg nightly, caused a fall in steady‐state plasma warfarin concentration ranging from 5% to 64.5% in 6 patients. There was no correlation between the extent of this fall and either the plasma concentration of quinalbarbitone or the initial rate of warfarin metabolism. Increasing the dose of qUinalbarbitone to 200 mg nightly (2 patients) and 300 mg nightly (1 patient) permitted a study of the relationship between dose and degree of induction. By administration of varying doses of 4 inducing agents to rats and constructing a dose‐response curve, it was shown that phenobarbitone was a more potent inducing agent than quinalbarbitone, amylobarbitone, or antipyrine. Possible reasons for this include the longer plasma half‐life of phenobarbitone and the higher liver/plasma drug ratio. These data suggest that more information about the indUCing ability of drugs in man and animals can be derived by performing enzyme induction studies at several rather than at a single dose level.

The interaction between indomethacin and probenecid; A clinical and pharmacokinetic study

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas‐liquid chromatographie method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3‐wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 ± 213 hr ng/ml to 4,181 ± 384 hr ng/ml when probenecid was given, but there was no change in the plasma half‐life of indomethacin. There was a reduction in the mean plasma clearance of indomethacinfrom 174 ± 21 m/lkg/hr to 107 ± 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distributionfrom 0.927 ± 0.16 L/kg to 0.613 ± 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacinfrom 8,967 ± 867 µg/day to 4,760 ± 674 µg/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 ± 48 ml/min to 126 ± 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.

Reduction of the enterohepatic circulation of norethisterone by antibiotics in the rat: correlation with changes in the gut flora.

When bile containing tritiated conjugates of norethisterone, collected from donor rats, was infused either into the duodenum or caecum of recipient rats, 23.5% and 42.4% of the dose was excreted in the bile respectively. Pretreatment of recipient rats with ampicillin or neomycin (200 mg/kg/day for 4 days) or neomycin + lincomycin (100 + 100 mg/kg/day for 4 days) significantly reduced (P < 0.001) the amount of steroid appearing in the bile of recipient rats following intracaecal administration of conjugates. There was a correlation between the reduction in enterohepatic circulation (EHC) and suppression of the gut flora. Ampicillin treatment caused a reduction in the anaerobic element and partial suppression of aerobes. Neomycin pretreatment caused a great reduction in the aerobic flora, but only a small reduction in anaerobes. Following neomycin + lincomycin treatment both the aerobic and anaerobic flora were dramatically reduced. Rifampicin treatment (200 mg/kg/day for 4 days) did not cause a reduction in the EHC of norethisterone, or in the concentration of aerobic or anaerobic flora in the caecum. However, the aerobic flora were rifampicin resistant. To investigate the onset of this resistance recipient rats were treated with rifampicin for 1, 2 or 3 days and a graded effect both on the EHC of the steroid and the incidence of resistant organisms was evident. Following ampicillin administration (4 days) both the EHC and the gut flora were normalized 14 days after the final drug treatment.

The plasma half lives and the pharmacological effect of the enantiomers of warfarin in rats

Abstract The anticoagulant potency of (-)- warfarin is 6.6 times greater than that of (+)- warfarin in male rats. This difference is partly explained by a difference in the plasma half life of the two enantiomers, 15.4 ± 2.8 hours for (-)- warfarin and 8.6 ± 1.6 hours for (+)- warfarin and partly by a difference in the inhibition of prothrombin complex synthesis; (-)- warfarin being 1.9 times more potent than (+)- warfarin.