Effect of food on the comparative pharmacokinetics of modified-release morphine tablet formulations: Oramorph SR and MST Continus.

The relative bioavailability and pharmacokinetic profiles of Oramorph SR (OSR) and MST Continus (MST), were evaluated by a randomized, four-way cross-over study in 24 healthy, male volunteers given single oral (30 mg) doses whilst fasting or after a high-fat breakfast. Mean Cmax, tmax, AUC (0,24h), AUC and tlag were significantly greater in fed compared with fasting subjects. Overall relative bioavailability of the two formulations (log AUC), was within the acceptable 80-125% limits for bioequivalence both fed and fasting. Mean fasting Cmax for OSR was greater than MST (P < 0.05) but there was no difference between formulations in mean fed Cmax. No statistically significant difference between OSR and MST was found for other parameters nor in the incidence of adverse events. These results suggest that OSR and MST are bioequivalent and that if patients were to transfer between formulations, dosage adjustment would be unnecessary, irrespective of their meal schedules or food intake.

Hormone replacement therapy by the transdermal administration of oestradiol and norethisterone.

The objective was to assess the efficacy and acceptability of a new transdermal norethisterone device as part of a hormone replacement therapy (HRT) regimen. The design was an open prospective clinical assessment for 6 months. The setting was the Academic Unit of Obstetrics and Gynaecology, Royal London Hospital, Whitechapel, London. Eighteen patients of confirmed menopausal status were recruited. Therapy consisted of continuous application of Estraderm TTS 50 (Ciba Laboratories) for a 28-day period, with the additional application of two norethisterone acetate patches in the last 12 days of this period. This schedule was repeated for six cycles. The main outcome measures were symptom and menstrual data--haematological indices, hepatic and renal function; lipid parameters; endometrial biopsy. The results showed a significant improvement in the patients' symptoms of hot flushes and sweating (P = 0.03). Of the 15 women who completed at least 6 months of medication, withdrawal vaginal bleeding was established at regular intervals in 9. One patient had a local irritant reaction to the patch. There were no significant changes observed in haematological indices, hepatic and renal function. There was a slight but not statistically significant decrease in the HDL cholesterol fraction when the patient was in the norethisterone phase of the cycle, but no change was observed between the beginning and end of the study. Histological examination of the endometrial biopsies showed features of secretory activity in 56% of samples after 6 months. There was no evidence of hyperplasia, pre-malignant or malignant changes in the remaining biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)

[Oral contraceptive steroid plasma concentrations in smokers and non-smokers (author's transl)]. / Concentrations plasmatiques des contraceptifs steroidiens oraux chez les fumeuses et les non fumeuses.

PIP: There are about 80 million women who use oral contraceptives (OCs). Several studies have shown that cardiovascular risk is increased 5 times in women who smoke and use OCs. To verify whether smoking can influence the metabolism of OCs the authors observed 311 OC users, of whom 102 were smokers, and 209 were not. The subjects were grouped according to time since the last pill was taken, and the data were subjected to analysis of weight and age covariates. Plasma concentrations of norgestrel and ethinyl estradiol were measured in all patients. There were no significant differences in steroid plasmatic concentrations in the 2 groups, and it appears that weight, age, and time since last pill have little influence on steroid level. The plasmatic concentration of thiocyanate, which is an indicator of the importance of tobacco absorption, did not present any significant statistical correlation either with ethinyl estradiol or with norgestrel. It appears that contraceptive steroids fall in the group of drugs whose rate of metabolism is not altered by ciagarette smoking.^ieng

Oral contraceptive steroid plasma concentrations in smokers and non-smokers.

A study was performed to find out whether the overall rate of metabolism of oral contraceptives is affected by smoking and whether this explains the increased incidence of cardiovascular disease in users of oral contraceptives who smoke. Plasma ethinyloestradiol and norgestrel concentrations in 311 women using oral contraceptives were similar in smokers and non-smokers. The overall rate of metabolism of contraceptive steroids does not therefore seem to be affected by cigarette smoking.

Studies on the enzymatic cleavage of norethisterone oenanthate.

Norethisterone oenanthate (NET OEN) was extensively hydrolysed in rabbit, rat and guinea pig plasma (99.9%, 76.1% and 46.0% hydrolysed in 90 min, respectively). In contrast, there was negligible hydrolysis (less than 2.5%) in dog, goat and human plasma. Rabbit liver, kidney, gut wall, stomach, heart and muscle showed marked hydrolytic activity in vitro, but there was little hydrolysis of NET OEN by either human muscle or fat. It is proposed that following intramuscular administration of NET OEN to rabbits, the ester is rapidly hydrolysed at the injection site and in the circulation whereas in humans the liver is the main site of hydrolysis since neither muscle nor plasma cause significant breakdown of the ester. The rabbit is not a good model for predicting the pharmacokinetics of NET OEN in humans.

Interindividual variation and drug interactions with hormonal steroid contraceptives.

Large interindividual differences occur in the plasma concentration of contraceptive steroids. With the present tendency to decrease the dose of progestagen and oestrogen any factor which reduces the bioavailability of the lower dose preparations becomes very important. The possibility that other drugs and environmental chemicals may interact with contraceptive steroids is currently being investigated. Clinical reports suggest that the most important interacting drugs are the antituberculosis agent rifampicin, anticonvulsants and antibiotics. In the case of the first two, evidence is available suggesting that microsomal enzyme induction, either in the liver or the gut wall, is the operative mechanism. Antibiotics interfere with the pharmacokinetics of contraceptive steroids by interfering with their enterohepatic circulation in animal species: whether this is operative in man is still unclear. Other environmental and constitutional factors such as smoking, variations in diet, and concurrent disease may alter the disposition of contraceptive steroids and affect response accordingly. Additional studies are needed to estimate the significance of such interactions.

PIP: There has been little study on the clinical pharmacology of OCs (oral contraceptives). Studies have shown that large interindividual differences occur in the plasma concentration of contraceptive steroids, indicating a difference in metabolism. As estrogen and progestogen content of OCs are being continually lowered, any substance which reduces the bioavailability of the steroids within OCs may actually lower contraceptive efficacy also. The literature is studied for mention of drug and other environmental chemical interactions with OCs. 3 main groups of drugs have been shown to react adversely with OCs: 1) antituberculous drugs, especially rifampicin; 2) anticonvulsant drugs; and 3) antibiotics. Studies on all 3 of these types of drugs are cited along with advice to patients concerning each category of drug. For the 1st 2 types of drugs, microsomal enzyme induction in either the liver or the gut wall is the operative mechanism. Antibiotics interfere with enterohepatic circulation in animal species. It is believed that smoking and diet may also affect the efficacy of OCs. Probably only individuals with low plasma concentrations of the contraceptive steroids are at serious risk from drug and environmental interactions.

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

The pharmacokinetics of a large (3 mg) oral dose of ethynylestradiol in women.

Plasma levels of ethynylestradiol (EE), EE sulphate (EES), EE glucuronide (EEG) and prolactin were measured in women up to 72 h following the oral administration of 3 mg of EE. The decline in plasma EE levels showed a sharp discontinuity at 10 h which is assumed to be due to the beginning of enterohepatic circulation (EHC). After this event, an apparently terminal monoexponential decline was eventually established with a half-life of 13.1 h. As a result of EHC, the volume of distribution was increased by 60% to 6.0 1.Kg-1 but it does not appear that any significant accumulation of EE would occur during multiple dosing. Plasma levels of EES were, on average, 22.5 times greater than those of EE and this circulating metabolite may act as a reservoir of EE. No circulating EEG could be detected. Comparing these results with those previously obtained with 50 microgram EE, there was no evidence of dose dependency in the pharmacokinetics of this steroid. Plasma prolactin levels were markedly enhanced by this single dose of oestrogen.

PIP: To test the effects of Progynon M, a postcoital contraceptive used in Tubingen where these studies were carried out, 6 female volunteers, aged 20-30 years, with no previous use of this or other hormonal medication and in good health, were dosed with 3 mg of EE (ethinyl estradiol) on Day 25 of menstrual cycle. Blood samples were removed hourly for 4 hours, and then at 4, 6, 8, 10, 12, 16, 24, and 48 hours after dosing. Plasma levels of EE, EE sulfate, EE glucuronide, and prolactin were measured. EE levels declined and showed sharp discontinuity at 10 hours postdosing, possibly due to the initiation of enterohepatic circulation (EHC). Once the EHC had begun, a monoexponential decline was established for EE with a half-life of about 13.1 hours. Because of EHC, the volume of distribution was increased by 60%; it is theorized, however, that multiple dosing with EE would not result in accumulation of the steroid. EE sulfate levels in plasma were 22.5 times greater than EE, leading to the postulation that EE sulfate is the reservoir for EE. EE glucuronide was not detected. The results reported for this study were compared with previously reported results of metabolite action of EE, and like an earler trial of 50 mcg of EE, there was no evidence of dose dependency in the pharmacokinetics of EE. Plasma prolactin levels jumped after EE dosing.

The effect of rifampicin on 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.

PIP: 7 female patients between ages 18-42 who were receiving treatment with rifampicin (450-600 mg daily) for tuberculosis were given a single dose of Minovlar (50 mg ethynlestradiol (EE) and 1 mg norethindrone acetate) and given a dose 1 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 0.01). The terminal plasma half-life increased from 2.9 + - 0.8 h to 6.3 + - 1.4 h (p 0.005). The sex hormone binding globulin capacity was reduced from 213.4 + - 11.5 nmoles to 129.0 + - 7.7 nmoles-1 after stopping rifampicin. In 1 patient starting rifampicin who was taking Minovlar as a long-term contraceptive, a decline in the plasma EE concentration was associated with an increase in the plasma follicle stimulating hormone concentration. Women taking oral contraceptive steroids and rifampicin at the same time are likely to suffer a decrease in the effectiveness of the OC. It is suggested that it is unwise for women taking rifampicin to use OCs as the sole method of contraception.

An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay.

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 concentration of EE rise to a peak of 128 pg/ml following the oral administration of 50 microgram 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.

PIP: A radioimmunoassay for ethinyl estradiol (EE) was developed and fully evaluated. It is applicable to plasma samples obtained after administration of oral contraceptives containing norethindrone or norgestrel in addition to EE. In addition, the bioavailability of EE, by comparison of its pharmacokinetics after intravenous and oral ingestion, was determined. Plasma concentrations of EE rose to a peak of 128 pg/ml after oral doses of 50 mcg of EE. After the intravenous administration of 50 mcg of EE, plasma levels of the steroid declined biexponentially; respective half-lives for the 2 routes were .83 and 6.75 hours. By comparing these route-of-administration results, the bioavailability of EE was determined to be 42%. EE thus has a lower bioavailability than norethindrone, yet the pharmacokinetics of the 2 steroids, including half-lives, plasma clearance, and volume of distribution, were similar. A secondary peak occurred in plasma at about 12 hours after dosing, giving strong evidence that EE undergoes enterohepatic circulation in women, an event of considerable clinical significance. The most distinctive feature of the radioimmunoassay used in this study is the use of partition between methanol/water and petroleum ether to remove excess fats from the initial ether extract. The inter- and intraassay precision of this newly developed method were within the range that is normally expected of such an assay.

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.

First-pass effect of norethindrone in rabbits and rats.

The influence of the route of administration on the pharmacokinetics of the synthetic progestogen norethindrone was studied in the rabbit and rat. In the rabbit, the area under the curve (AUC) after oral administration was 54% of that after i.v. administration. In the rat, the AUC after administration into the hepatic portal vein was 32% of AUCi.v.; after oral administration the AUCoral was 13.7% of AUCi.v. and 57.6% of AUCportal. Therefore, in both the rabbit and rat norethindrone is subject to a first-pass effect. Using the technique of constant withdrawal of blood from the hepatic portal vein after drug administration into the gastrointestinal tract, it was shown the norethindrone is metabolized in the gut wall. Hence, in the rat at least, there are both intestinal and hepatic components of the overall first-pass effect. In addition, increasing the time of intraportal injection from 15 sec to 2 min (thereby reducing the rate of drug delivery to the liver) resulted in the AUC being reduced by 40%. Dose-dependent kinetics were observed with doses of norethindrone greater than 500 microgram/kg.