B.S.Narasinga Rao

Pharmacokinetics of norethindrone in Indian women

Pharmacokinetics of norethindrone (NET) was evaluated in eleven women belonging to a low socio-economic group and in five womem belonging to the high socio-economic group after the administration of an oral dose of 0.35 mg NET minipill on an empty stomach. Blood samples were collected at different intervals of time over a period of 24 hours. Plasma NET was estimated by radioimmunoassay. In all women, peak levels of NET occurred within 1-2 hours and a semi-log plot of plasma NET levels showed a biexponential decline. The half-life of plasma NET clearance was relatively shorter in women of low socio-economic group with poor nutritional status as indicated by anthropometric indices, as compared to that in well nourished women of high socio-economic group. There was a significant positive correlation between weight/(height) 2x 100 index on the one hand and t1/2 (beta) on the other in all the women studied, thereby suggesting a role for nutritional status in the metabolic handling of NET.

Pharmacokinetics of levonorgestkel in Indian women belonging to low socio-economic group

This study attempted to evaluate the effect of nutritional factors on the disposition of levonorgestrel (LN), as administered in a combination oral pill. Plasma samples from 11 low socioeconomic women were measured by radioimmunoassay after oral doses of 2 types of combination oral formulations, Primovlar-30 (500 mcg of LN and 30 mcg of ethinyl estradiol) and WHO-LNB (150 mcg of LN and 50 mcg of ethinyl estradiol). The following data suggest that nutritional status as reflected by anthropometry can modify the disposition of LN in women. With both preparations, plasma levels of LN reached a peak from 1-2 hours after administration and ranged from 4.6-16.2 ng/ml with Primovlar-30 and 2.8-14.4 ng/ml with LNB. The amount of LN in circulation at 48 hours was found to be more than .5 ng/ml. A triphasic decline in plasma levels of the steroid was established. Pharmacokinetic parameters calculated by graphical and regression analyses showed that the elimination half-life of the LN had a positive correlation and the peak plasma concentration a negative correlation with the 2 anthropometric indexes: weight/height sq. times 100 and skin-fold at triceps.

Plasma levels of norethindrone in indian women receiving norethindrone enanthate (20 mg) injectable

Plasma norethindrone (NET) and progesterone were estimated by radioimmunoassay in seven Indian women after intramuscular administration of 20 mg NET enanthate. One subject had intermenstrual bleeding throughout the cycle. Out of the six subjects considered for analysis, three subjects showed ovulation suppression, two had delayed ovulation and the remaining one exhibited normal ovulatory pattern. Post-peak average plasma NET values ranged from 1.0 to 2.1 ng/ml. These values showed a significant positive correlation with the anthropometric indices such as body weight and mid-arm-circumference. The subjects with lower anthropometry showed exponential decline of plasma NET. A possible role for nutritional status of an individual in drug disposition is indicated from this study.

Effect of food restriction (undernutrition) on pharmacokinetics of levonorgestrel in rabbits.

Twelve female rabbits aged about 3-4 months were randomly divided into two groups (group A and group B) and were individually matched for their initial body weights. Animals of group A received a stock diet ad libitum while each of the animals in group B were fed 50% of the diet consumed by the corresponding matched control from group A. Pharmacokinetics of levonorgestrel were determined in all animals between 1 1/2-2 months after these diets were started, using an intravenous dose of 8-20 /uCi of 3H-levonorgestrel and 15-20 /ug of levonorgestrel per kg body weight. Urinary excretion of radioactivity was also measured in all the animals for a period of 5 days following the dose. The body weights of animals on the restricted diet were 17% lower than those of the ad lib fed animals. Haemoglobin levels and plasma albumin concentration were found to be in the normal range in both groups. There was a significant increase in Metabolic Clearance Rate (MCR) and t 1/2 pi and a decrease in elimination half-life in animals of group B as compared to those seen in animals of group A. The urinary excretion of label was found to be slightly increased in group B animals as compared to that in group A controls.

The rabbit as an animal model to study pharmacokinetics of levonorgestrel in women

In an attempt to develop an animal model to facilitate investigations on the effects of various nutritional and environmental factors on the metabolism of the contraceptive steroid levonorgestrel, the pharmacokinetics of levonorgestrel were investigated in rabbits. Six adult female rabbits received an intravenous bolus dose of 3H-levonorgestrel, 8-20 microCi, with 15-20 micrograms of carrier cold levonorgestrel per kg body weight. Blood samples were drawn at different intervals of time after the dose and the plasma drug concentration was determined both by radioisotopic dilution method and by radioimmunoassay. Plasma concentrations of levonorgestrel as assayed by radioimmunoassay agreed very closely with those obtained by isotope counting. The decline in plasma radioactivity attributable to unchanged levonorgestrel followed a triexponential pattern. Plasma radioactivity data were therefore analysed according to a three-compartment open model by graphical and regression analysis. The half-lives of the three phases pi, alpha and beta representing the shallow, deep peripheral and the terminal elimination compartment, respectively, were in close agreement with those reported in women. The metabolic clearance rate (MCR) and volume of distribution (VB) of levonorgestrel expressed per unit of body weight were comparable to values reported in women. The overall observed trend of pharmacokinetics of levonorgestrel in rabbits resemble closely those seen in women. It would therefore appear that the rabbit is a suitable animal model for studying the effects of nutritional factors on the pharmacokinetics of the drug.

Effect of food restriction (undernutrition) on pharmacokinetics of norethindrone in rabbits

Our previous studies have shown that the plasma norethindrone (NET) elimination is faster in women of low socio-economic group as compared to those of high socio-economic group. Undernutrition being very common in low socio-economic group, using an animal model, efforts were made to determine whether these differences were due to differences in the nutritional status of these two group of women. The experimental animals consisted of a set of twelve female rabbits, divided equally into two groups. One group (A) was fed on a stock diet ad libitum while the second group (B) received the diet in restricted amounts (half of that consumed by animals of group A). At the end of three months, radiolabelled NET was administered intravenously and plasma drug levels were determined at frequent intervals up to 24 hours. The plasma values were subjected to pharmacokinetic analysis. Food restriction to the extent of 50% resulted in a 20% deficit of body weight as compared to controls. The half-lives of alpha and beta phases were shortened in the restricted group resulting in an enhanced metabolic clearance rate of NET in this group. Though the differences were not statistically significant, the volume of distribution tended to be lower and the dose excreted in urine higher when food restriction was imposed.

Pharmacokinetics of norethisterone and levonorgestrel in experimental iron deficiency anemia in rabbits.

Mild-moderate anemia (hemoglobin, 10-12 g/100 ml) was induced in eight female rabbits by feeding a purified diet with low iron content over a period of 4 months and it could be maintained for a further period of 7 months. Nine control animals received the same diet supplemented with iron. Pharmacokinetics of intravenously administered contraceptive steriods, norethindrone and levonorgestrel, were determined in both control and anemic rabbits at the end of 150 and 171 days, respectively. No significant alterations were observed in the disposition of these steroids in deficient rabbits as compared to controls, indicating that mild-moderate forms of iron deficiency anemia may not influence the metabolic handling of either norethindrone or levonogestrel.

Effect of food restriction (undernutrition) on plasma sex hormone binding globulin (SHBG) capacity, liver drug metabolizing enzymes and uterine cytosol progesterone receptor levels in rabbits

The present investigation was designed to understand the mechanism underlying the altered pharmacokinetic and pharmacodynamic properties of norethindrone and levonorgestrel observed in undernourished rabbits. Eighteen albino rabbits aged 3-4 months were divided into two groups. One group received a stock diet ad libitum and the other group was individually fed half the food consumed by the matched animal in ad lib group. Three pairs of animals were sacrificed at the end of three months and the remaining at the end of five months. Liver and uterine tissues were dissected out and processed for analysis. For both sets of animals, whether killed at the end of three months or 5 months, the trend of results obtained were similar. The capacity and affinity characteristics of plasma sex hormone binding globulin were found to be not significantly different between control and experimental animals. The specific activities of liver microsomal glucuronyl transferase and cytochrome P-450 were significantly higher in undernourished rabbits. The increase observed in the activity of sulfuryl transferase was, however, not statistically significant. Uterine cytosol progesterone receptor levels were found to be higher in food restricted animals though there were no changes in the affinity properties of the receptors. Thus, it appears that imposition of food restriction leads to increased drug metabolism as a result of increased drug metabolizing enzyme activities and that the animals appear to adapt by enhanced target organ response in terms of elevated receptor concentration.

Pharmacokinetics of levonorgestrel in Indian women.

SummaryA low dose combination pill containing levonorgestrel 150 µg and ethynylestradiol 50 µg was administered orally to 13 women. Based on their anthropometric index they were classed as well-nourished (Group A) or undernourished (Group B). Plasma levels of levonorgestrel at various intervals after dosing were analysed by a specific radioimmunoassay and its pharmacokinetic parameters were computed. Peak plasma levels in both groups occurred within 2 h and the absorption half-lives were also similar. The decline in plasma levonorgestrel showed a tri-exponential decline in all Group A women, whereas it was biphasic in most of Group B. The π t1/2 was lower in Group A women and the α-phase was found to be negligible in Group B. A significant positive correlation between elimination half-life (β t1/2) and some of the anthropometric indices suggests a possible role of nutritional status in the metabolic handling of levonorgestrel.

BIOAVAILABILITY OF 'LEVONORGESTREL FROM INTRAVAGINAL RINGS IN WOMEN OF LOW INCOME GROUPS

Two types of intravaginal rings (IVR) containing 50-128 mg of levonorgestrel (LNOG) and 28-60 mg of estradiol were inserted in 18 apparently normal subjects belonging to the low socioeconomic group on day 5 of the cycle. A total of 120 cycles were studied with cyclic insertion and withdrawal. Data on menstrual cycle changes were noted. For bioavailability study, blood samples were collected twice weekly for a period of one month in the first cycle in 8 women. All the plasma samples were analysed for LNOG and progestrone by RIA. Cycle control was excellent in IVR users. Expulsion of the ring was noted in 4 instances. The plasma LNOG levels were found to reach a peak level ranging from 2.7-7.5 ng/ml within 4 days after the IVR insertion. In between day 9 to 24, the plasma levels appeared to be almost steady, and once the ring was removed, the levels dropped off rapidly. The mean plasma LNOG calculated during the steady-state period of the cycle ranged from 1.6-5.1 ng/ml. These mean LNOG levels were found to be inversely correlated with skin-fold at triceps. In all the subjects ovulation was found to be inhibited, as reflected by plasma progesterone values. The range of release rates calculated from plasma steady-state values was 51-119 micrograms/day. The average release rates over the entire period of observation based on area under curve were 102-200 micrograms/day. On the other hand, the release rates obtained from the residual drug in the ring after a period of use ranged from 184-259 micrograms/day.