Investigation into the age-dependence of the pharmacokinetics of cyproterone acetate in healthy male volunteers.

OBJECTIVE: To investigate a possible age-dependence of the pharmacokinetics of cyproterone acetate following single oral administration. METHODS: Twenty eight healthy men between 22 and 74 years of age received a single oral dose of 100 mg cyproterone acetate. The pharmacokinetic parameters, area under the serum concentration-time curve, apparent volume of distribution, apparent clearance, terminal half-life and the concentration ratio of 15 beta-hydroxycyproterone acetate/cyproterone acetate were examined for possible age-dependence using regression analysis. RESULTS: The values of area under the serum level-time curve showed high interindividual variability and were not related to age. With regard to apparent clearance and volume of distribution, decreasing and increasing values, respectively, were observed with increasing age. There was also a clear dependence of the terminal half-life on age. Elderly men had values about two times higher (95 h) than men belonging to the younger age groups (45 h). The mean concentration ratio of 15 beta-hydroxycyproterone acetate/cyproterone acetate was 0.8 (0.3) and showed no age-dependent change. CONCLUSIONS: Apparent clearance and apparent volume of distribution of cyproterone acetate showed age-dependent changes. Combined, the two effects cause a clear age-dependence of the terminal half-life of cyproterone acetate. An age-related reduction in liver volume is thought to be mainly responsible for the decrease in hepatic clearance with age. Chronic daily administration of the drug to elderly men may therefore lead to somewhat higher steady-state concentrations in the serum than in young men receiving the same dose.

Comparative pharmacokinetics of two new steroidal estrogens and ethinylestradiol in postmenopausal women.

It was the aim of the study to compare the pharmacokinetic properties of the two new estrogens, ZK 136295 and ZK 115194, with those of ethinylestradiol (EE2) after single intravenous (60 micrograms) and oral (120 and 240 micrograms) administration in 54 postmenopausal women. In particular, our objective was to examine whether one or both compounds were characterized by an improved oral bioavailability with less inter-subject variability than EE2. Drug serum concentrations were determined using specific radioimmunoassays for EE2 and ZK 136295, and a GC/MS/MS-method for ZK 115194. Following i.v. administration of the new estrogens and of EE2, the drugs were rapidly distributed in the body. The mean terminal half-lives were calculated to be 12.3 +/- 12.4, 28.7 +/- 9.6, and 26.1 +/- 11.1 h for ZK 136295, ZK 115194, and EE2 respectively. After oral administration of 120 micrograms, the absolute bioavailability was calculated to be about 40% for ZK 136295 as well as for EE2 with a high inter-individual variation (variation coefficient: 44 and 67%). By doubling the dose, the systemic availability increased dose-dependently for both drugs to about 70% with the same high inter-individual variation. Following single oral administration of 240 micrograms ZK 115194, the absolute bioavailability amounted to 33 +/- 19%. The present study clearly revealed that although the two new estrogens differed considerably in their pharmacokinetic behavior, they demonstrated a reduced and highly variable systemic availability similar to that of EE2.

PIP: Researchers with the pharmaceutical manufacturer Schering AG in Berlin, Germany, conducted a double-blind clinical trial in 54 healthy, postmenopausal women to compare the pharmokinetic properties of two new estrogens (ZK 136295 and ZK 115194) with those of ethinyl estradiol (EE2). Specifically, they examined whether one or both of the new estrogens improved bioavailability with less inter-subject variability than EE2. The dosage included single intravenous (60 mcg) and oral (120 and 240 mcg) administration. ZK 115195 differs from natural estradiol by 14alpha, 17alpha-bridging, which should prevent early metabolic degradation during absorption and passage through the liver. ZK 136295 is the corresponding derivative of endogenous estriol. All three compounds were rapidly distributed throughout the body. ZK 136295 had the shortest mean terminal half-life; ZK 115194 had the longest (12.3 vs. 28.7 hours); and EE2 had a mean terminal half-life of 26.1 hours. Oral administration of 120 mcg effected an absolute bioavailability of about 40% for ZK 136295 and EE2. The inter-individual variation was high (variation coefficient = 44% and 67%) for both compounds. When the oral dose was 240 mcg, systemic availability increased dose-dependently for ZK 136295 and EE2 to around 70% with the same high inter-individual variation. Oral administration of 240 mcg of ZK 115194 effected an absolute bioavailability of about 33%. These findings show that the 14alpha, 17alpha-bridging of estradiol does not result in a higher bioavailability than that achieved by introduction of a 17alpha-ethinyl group. Yet, increasing the dose of ZK 115194 and of EE2 from 120 to 240 mcg increased their absolute bioavailability two-fold. In conclusion, even though the pharmacokinetic behavior of the two new estrogens differed markedly, the two estrogens exhibited a reduced and highly variable systemic availability similar to that of EE2.

Pharmacokinetics of levonorgestrel in 12 women who received a single oral dose of 0.15 mg levonorgestrel and, after a washout phase, the same dose during one treatment cycle.

The pharmacokinetics of levonorgestrel (LNG) was determined in 12 healthy women (age 21 to 33 years), following single dose administration of 0.15 mg LNG. The same preparation was also administered during one treatment cycle after a washout phase of 1 week. After single dose administration, maximum concentrations of LNG in the serum were 4.3 +/- 1.3 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.6 +/- 0.2 h and 13.9 +/- 3.2 h, respectively. The clearance was calculated to be 1.5 +/- 0.6 ml x min-1 x kg-1. The free fraction of LNG was 1.1 +/- 0.1% and the fractions bound to SHBG and albumin were 61.8 +/- 6.7% and 37.1 +/- 6.7%, respectively. There was a gradual decrease in serum trough levels of LNG from about 0.5 to 0.3 ng/ml during the cycle, and a concomitant decrease in SHBG concentrations in the serum by about 50%. Serum protein binding of LNG changed markedly during the treatment cycle. The free fraction increased to a value of 1.7 +/- 0.3%, the SHBG-bound fraction decreased to 42.0 +/- 11.4% and the albumin-bound fraction increased to 56.4 +/- 11.2%. Total serum clearance increased during the same time period from a mean value of 1.5 to about 2.5 ml x min-1 x kg-1. The clearance of unbound LNG, however, remained unchanged. An examination of the free LNG concentrations revealed the same time course of LNG trough levels during the cycle as the simulated curve. This was derived from the pharmacokinetic parameters which were obtained after single dose administration. Thus, the present study showed that the pharmacokinetics of LNG can be fully explained on the basis of single dose pharmacokinetics and the changes in serum protein binding which were caused by a reduction of SHBG levels in the serum during chronic treatment with LNG.

Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 9 healthy women (age 23 to 42 years), during a treatment period of three months with a low-dose oral contraceptive, containing 0.15 mg LNG together with 0.03 mg EE2 (Microgynon). After a wash-out period of 3 months, 8 of these women received a single administration of the same formulation. The results showed that there was an increase in serum trough levels of LNG, reaching steady-state in the second half of each treatment cycle. The LNG levels achieved were about 3 to 4 times higher than anticipated on the basis of single dose administration. At the end of treatment cycles one and three, the terminal half-life of LNG was in the range of 24-26 h, while a mean value of 20 h was observed following single dose administration. An EE2-induced increase in the SHBG concentration of about 50% as compared to pretreatment values was observed during a treatment cycle. Pretreatment values were reached following the drug-free interval of 7 days between two cycles. After single dose administration, the free fraction of LNG was 1.3 +/- 0.2% and the fractions bound to SHBG and albumin were 64.1 +/- 4.2% and 34.6 +/- 4.0%, respectively. Serum protein binding of LNG did not change during chronic treatment. An about 50% reduction in total and unbound clearance of LNG was observed during chronic treatment, as compared to single dose administration. Increased SHBG binding capacity and a reduced hepatic metabolic capacity were discussed as possible causes of accumulating LNG concentrations in the serum. On the last day of treatment cycles one and three, the AUC(0-24h) values of EE2 were 728 +/- 314 and 778 +/- 318 pg x ml-1 x h, respectively, and were in keeping with data reported from others.

PIP: Scientists at Schering AG Research Laboratories in Berlin, Germany, analyzed the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE2) in 23 to 42 year old women to study the effect of protein binding on the accumulation of LNG in the serum and to examine whether the clearance of free LNG changed during longterm use (3 treatment cycles) of a monophasic oral contraceptive (OC) with 0.15 mg LNG and 0.03 mg EE2. Blood samples were taken regularly to measure sex hormone binding globulin (SHBG) and LNG levels. During the 3-month treatment cycle, serum LNG trough levels rose until day 18, when they stabilized. LNG levels after a single dose of the OC were between 3 and 4 times greater than researchers expected. This higher dose may have been due to either EE2 or LNG impairing the hepatic metabolic capacity or there was an increase in serum SHBG binding capacity. The mean terminal half life of LNG after a single dose stood at 20 hours, whereas it was between 24 to 26 hours at the end of treatment cycles 1 and 3. EE2 increased the SHBG level around 50%. The free LNG fraction after 1 dose stood at 1.3%, while the LNG fraction bound to SHBG and to albumin stood at 64.1% and 34.6%, respectively. Longterm use did not affect serum protein binding of LNG. Between single dose and longterm administration, the total and unbound clearance of LNG fell around 50%. The area under the curve values of EE2 and 728 pg x ml-1 x hour at 0 hours and 778 pg x ml-1 x hour at 24 hour, which corresponded with data from other studies. These results indicated that the steady serum levels of LNG depend on the dose of LNG and are associated with the fall in total clearance, which in turn appear to be a mixture of changes in intrinsic clearance and changes in protein binding of LNG.

Pharmacokinetics of gestodene in 12 women who received a single oral dose of 0.075 mg gestodene and, after a wash-out phase, the same dose during one treatment cycle.

The pharmacokinetics of gestodene (GEST) was determined in 12 healthy women (age 22 to 34 years), following single dose administration of 0.075 mg GEST. The same preparation was also administered during one treatment cycle after a wash-out phase of 1 week. After single dose administration, maximum concentrations of GEST in the serum were 4.9 +/- 2.5 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.2 +/- 0.2 h and 14.9 +/- 6.7 h, respectively. The apparent clearance was calculated to be 0.8 +/- 0.4 ml x min-1 x kg-1. The free fraction of GEST was 1.3 +/- 0.3% and the fractions bound to SHBG and albumin were 64.3 +/- 10.7% and 34.4 +/- 10.4%, respectively. The results showed that there was a gradual decrease in serum trough levels of GEST during the cycle, due to a concomitant and equally high decrease in SHBG concentrations in the serum of about 26%. At the end of one treatment cycle, the free fraction of GEST increased to 1.8 +/- 0.5%, the SHBG-bound fraction decreased to 57.0 +/- 10.2% and the albumin-bound fraction increased to 41.3 +/- 9.9%. Total serum clearance increased during the same time period from a mean value of 0.8 to about 1.2 ml x min-1 x kg-1. The clearance of unbound GEST, however, remained unchanged. An examination of the free GEST concentrations revealed the same time course of GEST trough levels during the cycle as the simulated curve. This was derived from the pharmacokinetic parameters which were obtained after single dose administration. Thus, the present study showed that the pharmacokinetics of GEST can be fully explained on the basis of single dose pharmacokinetics and the changes in serum protein binding which were caused by a reduction of SHBG levels in the serum during chronic treatment with GEST. There was no evidence of GEST inhibiting its own metabolism.

Organ-specific and general tolerance of iotrolan 280 after intravenous administration: phase I study in healthy volunteers.

Iotrolan 280, the first water-soluble, nonionic, blood-isotonic, dimeric contrast medium, was administered intravenously to 12 healthy male volunteers. In a Phase I study with an intraindividual design in comparison with placebo, four doses between 0.15 and a maximum of 0.9 g I/kg body weight were administered in accordance with the principle of dose titration. The highest volume administered was 270.6 ml. The injection rate was 10 ml/min. The observation period was 5 days, with the exception of thyroid parameters (14 days). Iotrolan displayed good general and local tolerance. The typical side effects known from x-ray contrast media either did not occur or were minor after administration of iotrolan. No allergy-like reactions and no effects on hemodynamic parameters were observed. Although one observation is under discussion no effects of iotrolan on impulse generation and propagation in the myocardium could be confirmed. The blood and laboratory and chemical parameters analyzed showed no differences in comparison with placebo. In the treatment group with the highest dose (= 0.9 g I/kg body weight) there was one subject who showed a transient increase of the urinary glucose concentration and one case of a slight transient increase of the serum chloride concentration. No such side effects were seen in the subjects of the treatment groups with lower doses. All renal functions tests were normal. In this study iotrolan showed excellent tolerance after intravenous injection up to 0.9 g I/kg body weight.