Biopharmaceutical aspects of FK-506.

FK is a potent immunosuppressive agent. FK can be analyzed in biologic fluids by EIA. The oral absorption of FK is rapid but variable in dogs. After intramuscular administration, FK is slowly and continuously absorbed. FK is primarily eliminated by metabolism. Less than 1% of the administered dose is excreted in the bile or the urine. After chronic intramuscular administration FK inhibits drug metabolism. Monitoring of FK levels in plasma is essential for the proper interpretation of efficacy and toxicity studies.

Constituents of human meconium--I. Identification of 3-hydroxy-etianic acids.

The monohydroxylated fraction of bile acids of human meconium was analyzed by capillary GC-MS. In the sulfate-glucuronide fraction three saturated, and one unsaturated C20 steroidal acids were found. These acids were identified as 3 alpha-hydroxy-5 alpha-, 3 alpha-hydroxy-5 beta-,3 beta-hydroxy-5 alpha-androstane-17 beta-carboxylic, and 3 beta-hydroxyandrost-5-ene-17 beta-carboxylic based on the unequivocal GC-MS comparison with standards of all possible epimers at C-3, 5 and 17. The amount of the major C20 acid, 3 alpha-hydroxy-5 alpha-androstane-17 beta-carboxylic, in meconium was 0.2 nmol/g, i.e. 5 to 10 times the amount of lithocholic acid. To prevent the oxidation of 21-hydroxy-20-oxopregnanes to C20 acids meconium was extracted in the presence of sodium borohydride. In the absence of this reducing agent the amount of 3 beta-hydroxyandrost-5-ene-17 beta-carboxylic acid was increased and its 17 alpha-epimer could be detected. This indicates partial artifactual formation of this C20 acid from 21-hydroxypregnenolone, which is known to be present in human meconium. The amount of the saturated C20 acids was unaffected by the presence of sodium borohydride in the extraction medium, and their native occurence in human meconium was further confirmed by the absence of their 17 alpha-epimers in extracts obtained both with and without borohydride. The probable metabolic origin of C20 acids in the fetal-placental-maternal unit is discussed.

Patterns of hypothalamic-pituitary-gonadal dysfunction in men with liver disease due to differing etiologies.

The hypothalamic-pituitary-gonadal axis was evaluated in two groups of age-matched men with documented biochemical and histologic liver disease and compared to that of age-matched normal controls. Basal testosterone levels (p less than 0.05), spermatozoa concentrations (p less than 0.01), and seminal plasma volume (p less than 0.01) were reduced in the alcoholics studied with liver disease, but not the hemophiliacs with liver disease when compared to the normal controls. No difference in estradiol levels was noted between groups. Basal follicle-stimulating hormone and luteinizing hormone (LH) concentrations were increased (both p less than 0.01) in the alcoholics while only LH concentrations were increased (p less than 0.01) in the hemophiliacs compared to the normal controls. Gonadotropins (follicle-stimulating hormone and LH) and testosterone responses to clomiphene and to luteinizing hormone-releasing factor (LH only) in the alcoholic population studied, further distinguished the alcoholics from the hemophiliacs and the normal controls. The basal levels of the other anterior pituitary hormones (growth hormone and thyroid-stimulating hormone) as well as their provocative responses to thyrotropin-releasing hormone also distinguished the alcoholics from the hemophiliac population. Based upon these results, we propose that factors other than the liver disease per se are responsible for the disturbances of hypothalamic-pituitary-gonadal function observed in men with biochemically as well as histologically advanced stable liver disease.