Three-Level Hepatotoxicity Prediction System Based on Adverse Hepatic Effects.

Hepatotoxicity is a major cause of drug withdrawal from the market. To reduce the drug attrition induced by hepatotoxicity, an accurate and efficient hepatotoxicity prediction system must be constructed. In the present study, we constructed a three-level hepatotoxicity prediction system based on different levels of adverse hepatic effects (AHEs) combined with machine learning, using (1) an end point, hepatotoxicity; (2) four hepatotoxicity severity degrees; and (3) specific AHEs. After collecting and curing 15 873 compound-AHE pairs associated with 2017 compounds and 403 AHEs, we constructed 27 models with three end point levels with the random forest algorithm, and obtained accuracies ranging from 67.0 to 78.2% and the area under receiver operating characteristic curves (AUCs) of 0.715-0.875. The 27 models were fully integrated into a tiered hepatotoxicity prediction system. The existence of hepatotoxicity existence, severity degree, and potential AHEs for a given compound could be inferred simultaneously and systematically. Thus, the tiered hepatotoxicity prediction system allows researchers to have significant confidence in confirming compound hepatotoxicity, analyzing hepatotoxicity from multiple perspectives, obtaining warnings for the potential hepatotoxicity severity, and even rapidly selecting the proper in vitro experiments for hepatotoxicity verification. We also applied three external sets (11 drugs or candidates that failed in clinical trials or were withdrawn from the market, the PharmGKB (offsides) database, and an herbal hepatotoxicity data set) to test and validate the prediction ability of our system. Furthermore, the hepatotoxicity prediction system was adapted into a flow framework based on the Konstanz Information Miner, which was made available for researchers.

Insight into the negative effect and lipid profile alterations in liver of mice exposed to methylimidazolium ionic liquids, a novel "green" solvent.

Background: Ionic liquids (ILs) have been recognized as potential environmentally friendly solvents; however, their potential toxicity to living organisms warrants thorough investigation, particularly for novel-generation ILs in mammalian models. Methods: In this study, we examined the hepatic effects and disruption of lipid metabolism in mice exposed to 1-heptyl-3-methylimidazolium chloride (C7[MIM]Cl), a novel ILs. After four weeks of oral administration at different dosages (2.38, 5.95, and 11.9 mg/kg b.w.), we conducted clinical chemistry analysis and histopathological examination of the liver to assess biochemical and structural changes. Results: The low-dose C7[MIM]Cl group exhibited a significant increase in alanine aminotransferase (ALT) levels, while aspartate aminotransferase (AST) levels were elevated in both low-dose and high-dose groups without statistical significance. Histopathological examination showed inflammatory cell infiltration and red blood cell aggregation in the livers of mice exposed to C7[MIM]Cl, particularly in the high-dose group. Oxidative stress levels showed moderate changes in response to C7[MIM]Cl exposure. Notably, hepatic biochemical parameters revealed a dose-dependent increase in triglycerides (TG) levels with statistically significant differences compared to the control group (P ≤ 0.01). Targeted lipidomic analysis revealed notable alterations in liver lipids of mice exposed to C7[MIM]Cl, with lysophosphatidylethanolamine (18:0), phosphatidylcholines (18:0), and phosphatidylcholines (19:0) identified as critical lipids associated with C7[MIM]Cl exposure. Furthermore, metabolic pathway analyses demonstrated significant disturbances in the glycerophospholipid metabolic pathway. Conclusion: These findings provide valuable insights into the hepatic effects of C7[MIM]Cl exposure and novel perspectives on the disruption of lipid metabolism underlying ILs toxicity.

Tissue sites of alpha fetoprotein synthesis by the rat during pregnancy and hepatoma growth.

The tissue sites of alpha1 fetoprotein (AFT) synthesis by the rat during gestation and hepatoma growth were determined by specific incorporation of a radiolabeled amino acid precursor into AFP by tissue cultures in vitro. During gestation, AFP were produced by the yolk sac, the fetal liver, and in small amounts by the fetal gastrointestinal tract; there was no synthesis by maternal rat tissues. During growth of a transplantable hepatoma, only the hepatoma tissue synthesized AFP; the nontumor tissue of the host contained AFP but did not produce it.

PIP: Alpha fetoprotein (AFP) synthesis by adult rats during gestation and hepatoma growth was determined in vitro with specific precipitations of radiolabeled AFP antisera after incubation of Spinner cultures of various rat tissues in arginine-free culture medium containing radiolabeled arginine. In general, AFP was synthesized by fetal liver, yolk sac, small intestine, and transplantable (tumor) tissue; none of the normal adult tissues, including testis or ovary, produced AFP. AFP synthesis (measured over 22 hours) was confined to the fetal liver (367 ng), yolk sac (1,368 ng), and to a small extent, the gastrointestinal tract during 19-day gestation. None of the maternal tissues produced AFP. When measured during growth of a transplantable hepatoma, AFP was synthesized only by the hepatoma tissue, though the nontumor tissue of the host contained AFP, due to release of AFP from the cultured tissue as it degenerated in vitro, but did not produce it (noninvolved tissues of hepatoma-bearing rats did not incorporate labeled arginine into AFP in vitro). Identifying fetal organs responsible for AFP synthesis explains observed AFP concentration changes in the postpartum period in rats, since elevated AFP in the mother is caused by AFP produced by the fetus which crosses the placenta or yolk sac to maternal circulation. Elevations above normal (.06 mcg/ml) adult rat concentrations occur in 3 circumstances in the nonpregnant rat: 1) development of AFP-producing tumors; 2) proliferation by normal liver cells; and 3) exposure to chemical carcinogens.

The detection of alpha 1-fetoprotein in patients with viral hepatitis.

PIP: Alpha fetoprotein (AFP) was detected in sera (351 samples) of 128 patients with viral hepatitis by radioimmunoassay. 77 positive tests for AFP were obtained. These positive results were demonstrated on 1 or more samples taken from 40 (31%) of the 128 patients studied; the highest value obtained was 4400 ng/ml. Hepatitis B antigen (HBAg) was positive in 26/40 (65%) of patients in whom AFP was detected during the disease process. However, 58/88 (66%) who were seronegative for AFP also demonstrated HBAg in their sera. Chi-square analysis revealed no significant difference in occurrence of detectable AFP between HBAg seropositive and seronegative patients. Individuals seropositive for AFP had no statistically different concentration of the protein than patients seropositive or seronegative for HBAg. 24 patients' sera were tested serially over a 2-week period. Both the peak glutamic-pyruvic transaminase (GPT) and peak total bilirubin levels were in a higher range in those 10/24 patients seropositive (P .001) for AFP than in the 14/24 who were seronegative. Appearance of AFP was related to the severity of liver tissue destruction, as reflected by serum GPT. However, peak AFP levels were attained 5-16 days after peak serum GPT appeared in the circulation.^ieng

Early appearance of embryonic -globulin in rat serum during carcinogenesis with 4-dimethylaminoazobenzene.

PIP: Heptatic tumors were induced in male Donryo rats by feeding them a 4-dimethylaminoazobenzene diet to study the occurrence of serum alpha globulin (AG) in rats during carcinogenesis. AG was found in rat serum as early as the 3rd week after onset of feeding of the carcinogenic diet; this was designated the early-stage appearance. The embryonic protein was observed in 31 (76%) of 41 rats at the 6th week after diet introduction. Subsequently, concentrations of AG decreased, and by the 11th-12th week it disappeared from serum. After 13 weeks, the developmental protein reappeared in 27/33 rats, designated the last-stage appearance, and 26 of these animals developed hepatomas. Of the 22 rats in which AG appeared in the early stage, 20 (91%) developed hepatomas after 19 weeks. By the 6th week of the carcinogenic diet, the average serum level of AG was 2-4 mg/dl, but after 13 weeks, it reached 60-100 mg/dl, corresponding to the serum level of newborns. Since most of the rats in which AG appeared at the early stage developed hepatomas, the early appearance of the protein may be related to cancerization of liver cells; on the other hand, the early appearance of AG may simply reflect an acute liver lesion caused by the toxicity of 4-dimethylaminoazobenzene. All rats that developed hepatomas were AG positive.^ieng

Elevated concentrations of serum alpha-fetoprotein in rats with chemically induced liver tumors.

The study was undertaken to determine whether aflatoxin B1 (AFB1)-induced liver tumors in rats produced alpha1-fetoprotein (AFP) and whether the age of the animals would influence such as appearance, a finding suggested by data seen in man. Other liver carcinogens (N-hydroxy-N-2-fluorenylacetamide, N-2-fluorenylacetamide, and diethylnitrosamine) were tested for their ability to induce liver tumors producing AFP. The presence of AFP. The presence of AFP in the serum was determined by double diffusion in agarose and by comparison also by quantitative radioimmunoassay. Using double diffusion, AFP was detected in the majority of tumor-bearing rats that had received either N-2-fluorenylacetamide or N-hydroxy-N-2-fluorenylacetamide. Sera of diethylinitrosamine-treated rats with liver tumors were all positive, whereas sera of rats bearing AFB1-induced tumors were positive in only a few cases. However, all sera of tumor-bearing rats examined had elevated AFP levels by radioimmunoassay. Nonetheless, the average level of AFP in the sera of rats bearing AFB1-induced tumors was considerably lower, compared to the sera of rats with tumors caused by diethylnitrosamine, N-2-fluorenylacetamide, or N-hydroxy-N2-fluorenylacetamide. Rats started on AFB1 when 6 weeks old had more mixed liver tumors with neoplastic hepatocytes and bile ducts and higher AFP levels than did rats started at 26 weeks of age. However, the histological grade of differentiation of inducted tumors did not seem to influence the AFP level.

PIP: Based on findings suggested by data in humans, this study attempted to determine whether aflatoxin Bl (AFB1)-induced liver tumors in rats produced alpha fetoprotein (AFP) and whether the animal's age influenced such appearance. Other liver carcinogens such as N-hydroxy-N-2-fluorenylacetamide (h2-FAA), N-2-fluorenylacetamide (2-FAA), and diethylnitrosamine (DENA) were tested for their abilities to induce liver tumors which produced AFP. The presence of AFP in serum was determined by double diffusion in agarose and by comparison also with quantitative radioimmunoassay. Male Fischer 344/CS rats were used in all experiments. By double diffusion, the AFP was detected in a majority of tumor-bearing rats that had received either 2-FAA or h2-FAA. Sera of DENA-treated rats with hepatic tumors were all positive, whereas sera of rats with AFB1-induced tumors were positive only in a few cases. However, all sera of tumor bearing rats examined had elevated AFP levels when measured by radioimmunoassay. Still, the average level of AFP in sera of rats bearing AFB1-induced tumors was considerably lower when compared with sera of rats whose tumors were caused by DENA, 2-FAA, or h2-FAA. Younger rats suffered more severe alterations: rats started on AFB1 when 6 weeks old had more mixed liver tumors with neoplastic hepatocytes and bile ducts and higher AFP levels than did rats started at 26 weeks of age. However, histological grade of differentiation of induced tumors did not seem to influence the AFP level, although the DENA-treated rats usually had high levels of AFP and less differentiated tumors.

Early appearance of serum -fetoprotein as a function of dosage of various hepatocarcinogens.

PIP: A previously reported early appearance of alpha fetoprotein (AFP) in rats fed 3'-methyl-4-dimethylaminobenzene (3-MDAB) which was induced before definite cancers were formed and disappeared on cessation of 3-MDAB administration was further investigated using different doses of 3-MDAB as well as other hepatocellular carcinogens and hepatotoxic agents. AFP was induced after 3 weeks of ingestion of diets with 600 ppm 3-MDAB and appeared after only 2 weeks when higher doses (900 and 1200 ppm) were used. Lower levels of 300 ppm 3-MDAB gave only a transient appaerance of AFP, beginning at the 5th week and remaining detectable for 3 more weeks, but 150 ppm did not induce at all. Immunosuppression with rat lymphocyte globulin extended for 1 week the time during which positive AFP titers were maintained upon cessation of 3-MDAB (600 ppm) intake. A transient appearance of AFP was found when rats were given the carcinogens dimethyl-4-dimethylaminoazobenzene (4-DMAA; 600 ppm), aflatoxin (AFB1; 4 ppm), N-2-fluorenylacetamide (N-2-FAA; 200 and 300 ppm), and N-hydroxy-N-2-fluorenylacetamide (N-OHFAA; 213 and 320 ppm). Lower doses of AFB1 (.2 and 2 ppm), N-2-FAA (150 ppm), N-OHFAA, and diethylnitrosamine (40 ppm) did not induce detectable AFP levels in serum nor did 2'-methyl-4-DMAA (600 ppm) and CCl4 (50 mg intraperitoneally twice a week). Apparently, high levels of liver carcinogens are required to induce the early appearance, within 2-5 weeks, of detectable AFP in serum.^ieng

Early appearance of serum -fetoprotein during hepatocarcinogenesis as a function of age of rats and extent of treatment with 3'-methyl-4-dimethylaminoazobenzene.

PIP: The early appearance of serum alpha-fetoprotein (AFP) during hepatocarcinogenesis as a function of age of rats and extent of treatment with 3'-methyl-4-dimethylaminoazobenzene is reported. Administration of .06% of the benzene hepatocarcinogen in the diet of 6- to 12-week-old male rats led to the prompt appearance of AFP in the serum within 3-4 weeks. Discontinuation of treatment at Week 5 dropped the AFP in serum to undetectable levels within 2 weeks, and it remained negative over a 30-week period when, at autopsy, no liver cancer was found. Administration of azo dye to 6-week-old rats for 10 weeks also decreased AFP in serum to undetectable levels over the next 2 weeks, except in 2 of 45 rats who developed large hepatomas early and remained positive. In the remainder, AFP reappeared beginning at Week 15, and liver cancer was present at Week 20 except for 13 rats that remained negative, although 7 had hepatoma. The age of the rats played no marked role in the precocious appearance of AFP. The presence of AFP in each group was related to the histological picture of the liver at the time of autopsy. There was no detectable AFP in untreated control rats, nor was there any in rats fed .05% of the hepatotoxic but not carcinogenic alpha-naphthylisothiocyanate which led to extensive jaundice and bile duct proliferation.^ieng

Prolactin binding to R3230AC mammary carcinoma and liver in hormone-treated and diabetic rats.

Specific 125I-labeled prolactin binding was measured in membrane particles prepared from R3230AC mammary carcinoma and liver of tumor-bearing Fischer rats after either prolactin, estrogen, or lergotrile mesylate treatment, or after the induction of diabetes by streptozotocin. Hormone binding to tumors was decreased by treatment with prolactin (0.5 or 1 mg/day) or estradiol valerate (7.5 mg/kg/week). In contrast, prolactin treatment did not affect prolactin binding to liver membrane particles, but estradiol valerate treatment resulted in a four-fold increase in prolactin binding to this tissue. Lergotrile mesylate, which lowers plasma prolactin levels, did not affect tumor growth or prolactin binding to either tumor or liver. Prolactin binding to both tumor and liver was significantly reduced in diabetic rats, suggesting that insulin may play an important role in controlling tissue sensitivity to prolactin. Specific binding of 125I-labeled prolactin to enzymatically dissociated cells from R3230AC tumors was demonstrated in vitro. The binding capacity of the cells was found to be of the same order of magnitude as the binding capacity in membrane preparations when appropriate corrections were applied for yields of cells and membranes. R3230AC tumor, which is responsive to prolactin appears therefore to be a useful model system for further study aimed at elucidation of growth and metabolic response to the hormone prolactin in breast cancer.

PIP: Specific iodine-125-labeled prolactin binding was measured in membrane particles prepared from R3230AC mammary carcinoma and liver of tumor-bearing Fischer rats after either prolactin, estrogen, or lergotrile mesylate treatment, or after the induction of diabetes by streptozotocin. Hormone binding to tumors was decreased by treatment with prolactin (.5 or 1 mg/day) or estradiol valerate (7.5 mg/kg/week). In contrast, prolactin treatment was without affect on prolactin binding to liver membrane particles, but estradiol valerate treatment resulted in a 4-fold increase in prolactin binding to this tissue. Lergotrile mesylate, which lowers plasma prolactin levels, had no affect on tumor growth or prolactin binding to either tumor or liver. Prolactin binding to both tumor and liver was significantly reduced in diabetic rats, suggesting that insulin may play an important role in controlling tissue sensitivity to prolactin. Specific binding of iodine-labeled prolactin to enzymatically dissociated cells from R3230AC tumors was demonstrated in vitro. The binding capacity of the cells was found to be of the same order of magnitude as the binding capacity in membrane preparations when appropriate corrections were applied for yields of cells and membranes. R3230AC tumor, which is responsive to prolactin, appears therefore to be a useful model system for further study aimed at elucidation of growth and metabolic response to the hormone prolactin in breast cancer.

Statins and its hepatic effects: Newer data, implications, and changing recommendations.

Hepatic adverse effects are one of the most commonly known adverse effects reported with statins. Frequently, fear of serious hepatic effects contributes to underutilization of statins as well as unnecessary discontinuation of its use among those indicated. There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders. Based on reviewed literature, statins appear to be associated with a very low risk of true and serious liver injury. Unprecedented fears regarding hepatic adverse effects of statins among prescribers and patients can deny patients of the significant benefits of these agents. Routine periodic monitoring of liver function does not appear to detect or prevent serious liver injury and hence may not be indicated. But the potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice. Statin use need not be avoided in patients with preexisting liver dysfunction such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, compensated cirrhosis, and compensated chronic liver disease if its use is clearly indicated. Physician's judgment based on the risk and benefit for an individual patient does matter when a strategy is chosen regarding the use of statins and monitoring patients while on statins.

Alpha-fetoprotein in ontogenesis and its association with malignant tumors.

PIP: The major steps in development of ontogenesis and the role of alpha fetoprotein (AFP) synthesis are outlined. AFP is defined and its physiocochemical characteristics are described including methods of detection and identification. The liver and yolk sac of fetuses are shown as the principle sites of AFP synthesis in ontogenesis, and the dynamics of AFP in ontogenesis from the early embryonic period through midpregnancy to pregnancy termination to AFP shut-down in early postnatal period are displayed. AFP synthesis during regeneration of the liver provides the model for studying the nature of AFP production. The role of AFP in hepatocellular cancer receives a great deal of attention, focusing on the site of AFP synthesis in cancer of the liver; demonstration of AFP in blood of cases of hepatic cancer (and other diseases) by agar-gel precipitation; quantitative aspects of AFP production by liver tumors; and etiologic and pathogenic influences on AFP production by hepatomas. Clinical aspects of the diagnosis of liver cancer are reviewed. The occurrence of AFP with teratocarcinomas is remarked upon. The article's central objective was to emphasize the importance of basic research on AFP, especially the development of an accessible high-sensitivity test for use in broad epidemiological surveys. Experimental approaches to some immediate problems were formulated: 1) Is there any external factor controlling AFP synthesis and determining its intensity? 2) Is synthesis performed only by certain cell types or is AFP production inherent in any hepatocyte? 3) Is control of AFP synthesis accomplished by regulating the intensity of the process in individual cells or by involvement of a varying number of cells? And 4) is AFP synthesis in a tumor due to maintained ability of the stem tumor cell to differentiate or is it the result of dedifferentiation of the mature hepatocyte??^ieng

Risk factors for the spread of AIDS in rural Africa: evidence from a comparative seroepidemiological survey of AIDS, hepatitis B and syphilis in southwestern Uganda.

Before commencing rational control programmes for AIDS in Africa it is desirable to determine the relative importance of heterosexual and various non-sexual modes of transmission. We investigated this by comparing the seroepidemiologies of AIDS, hepatitis B and syphilis at two rural hospitals in southwest Uganda. During August 1986, 3% of 357 outpatients, reflecting the age and sex composition of the general population, were anti-HIV positive. Anti-HIV seropositivity, both in the outpatients and among 36 suspected prostitutes and 14 suspected AIDS cases, was confined to individuals aged 20 or over. For men, seropositivity was associated with sexual contact with prostitutes (a risk factor for 61% of young men in the study). In the prostitute group, 25% were anti-HIV positive and 46% were positive on the Treponema pallidum haemagglutination (TPHA) test for syphilis. The risk factors for HIV, but not hepatitis B, were the same as for having a history of sexually transmitted disease (STD). However, there was, surprisingly, an association between a history of STD and seropositivity for hepatitis B virus but not for HIV infection. The geographical and age distributions of seropositivity for HIV and hepatitis B virus were also quite different. Finally, blood transfusions, scarification and exposure to mosquitoes (as assessed by a history of malaria) were not evident risk factors for either HIV or hepatitis B virus. AIDS in rural Africa seems to differ in its epidemiology from hepatitis B and appears to be spread predominantly by pre-existing patterns of heterosexual activity responsible for high rates of other sexually transmitted diseases.

PIP: AIDS in rural Africa seems to differ in its epidemiology from hepatitis B and appears to be spread predominantly by preexisting patterns of heterosexual activity responsible for high rates of other sexually transmitted diseases. The authors compared the seroepidemiologies of AIDS, hepatitis B, and syphilis at 2 rural hospitals in southwest Uganda. During August 1986, 3% of 357 outpatients, reflecting the age and sex composition of the general population, were anti-HIV positive. Anti-HIV seropositivity, both in the outpatients and among 36 suspected prostitutes and 14 suspected AIDS cases, was confined to individuals aged 20 or over. For men, seropositivity was associated with sexual contact with prostitutes (a risk factor for 61% of young men in the study). In the prostitute group, 25% were anti-HIV positive and 46% were positive on the Treponema pallidum hemagglutination (TPHA) test for syphilis. The risk factors for HIV, but not hepatitis B, were the same as for having a history of sexually transmitted disease (STD). However, there was, surprisingly, an association between a history of STD and seropositivity for hepatitis B virus but not for HIV infection. The geographical and age distributions of seropositivity for HIV and hepatitis B virus were also quite different. Finally, blood transfusions, scarification, and exposure to mosquitoes (as assessed by a history of malaria) were not evident risk factors for either HIV or hepatitis B virus.

Imipramine disposition in users of oral contraceptive steroids.

Ten women on long-term, low-dose estrogen oral contraceptive steroids (OCS) and eight age-matched drug-free female controls received an intravenous infusion of 12.5 mg imipramine. Eleven (six OCS users and five controls) also took a 50-mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OCS and control groups and clearance was of the same order (899 and 975 ml/min). Elimination t1/2 was prolonged in OCS users after intravenous doses (17.8 vs 25.5 hr) but did not change after oral doses (18.4 vs 19.1 hr). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OCS users (from 27.1% vs 44.1%), which resulted in a trend toward decreased apparent oral clearance (from 4649 vs 2322 ml/min). Women who used OCS regularly show little change in imipramine kinetics after intravenous dosing. After oral dosing absolute systemic bioavailability increased, resulting in decreased apparent oral clearance in the absence of any change in oral elimination t1/2. Imipramine (with high first-pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These data are consistent with OCS inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OCS use.

PIP: 10 women on longterm, low dose estrogen oral contraceptives (OCs) and 8 age matched drug free female controls received an intravenous infusion of 12.5 mg imipramine. 11 (6 OC users and 5 controls) also took a 50 mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OC and control groups and clearance wa of the same order (899 and 975 ml/minute). Elimination 1/2-life was prolonged in OC users after intravenous doses (17.8 vs 25.5 hours) but did not change after oral doses (18.4 vs 19.1 hours). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OC users (from 27.1% vs 44.1%), which resulted in a trend towards decreased apparent oral clearance (from 4649 vs 2322 ml/minute). Women who used OCs regularly showed little change in imipramine kinetics after intravenous dosing. After oral dosing, absolute systemic bioavailability increased, resulting in decreased apparent oralclearance in the absence of any change in oral elimination 1/2-life. Imipramine (with high 1st pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These date are consistent with OC inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OC use.

Enzyme induction by oral testosterone.

Six normal male volunteers ingested a dose of 400 mg free testosterone daily as tablets over 21 days. By the end of treatment intravenous antipyrine half-life had decreased significantly from 8.0 +/- 2.7 to 5.7 +/- 2.6 hr. The subjects eliminated testosterone from serum more rapidly on the twenty-first day of testosterone ingestion than on the first day. Serum albumin, bilirubin, prothrombin, alanine-amino-transferase, and alkaline phosphatases were unchanged during the experiment. It is concluded that oral testosterone treatment induces the hepatic drug-metabolizing system including that of testosterone.

PIP: The effects of high doses of testosterone on liver function was studied in 6 healthy males. Intravenous antipyrine elimination was used as the primary parameter of liver function. The subjects received 400 mg testosterone orally for 20 days. The half-life of antipyrine decreased from a mean of 8 + or -2.7 to 5.7 + or -2.6 hours by the end of treatment. Excretion of testosterone was significantly (p greater than .0005) higher on Day 21 of the experiment than on Day 1. Treatment had no apparent effect on serum levels of albumin, bilirubin, prothrombin, alanine-amino-transferase, and alkaline phosphatases. It is concluded that orally administered testosterone induces its own enzymatic metabolism.

Biochemical, endocrine, and other indices during quinestrol therapy.

PIP: The effect of .025 mg quinestrol twice daily for 6 months was studied in 8 menopausal and postmenopausal women. There was no change in mean body weight, blood pressure readings, pulse rate or electrocardiograms. Vaginal smears showed an estrogenic effect of the drug which included cornification of the vaginal epithelium. There was a slight decrease in beta lipoproteincholesterol and serum acid phosphatase. There was an increase in serum creatine between the third and sixth months of treatment with no change in serum creatinine. In non-diabetic women, glucose-induced hypophosphatemia was accentuated. In diabetic women, the glucose tolerance appeared to improve. In both groups, increases in serum insulin caused by a glucose load were less under quinestrol therapy than without.^ieng

Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives.

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.

PIP: The effect of oral contraceptives (OCs) on hepatic drug elimination, in this case chlordiazepoxide, was studied in 11 healthy young men, 11 healthy young women, and 7 healthy young women receiving OCs for more than 6 months. Elimination half-life was longer (14.8-8.9 hours) and the protein binding less (95.5 and 97%) in women than in men. When weights were normalized, plasma clearances of total drug did not differ, but clearance of unbound drug was significantly less in women (8.7 ml/min/kg) than in men (15.6 ml/min/kg). Women taking OCs had a lower plasma binding (from 93.6-95.5%) and a higher volume of distribution (from .62-4 1/kg) than women not taking OCs. Elimination half-life was longer (from 23.4-14.8 hours) and clearance of unbound drug lower (from 5.7-8.7 ml/min/kg) in women on OCs than in those not using them, but these differences were not statistically significant.

Gossypol binds to a high-affinity binding site on human serum albumin.

The triterpene gossypol competes with bilirubin for a high-affinity binding site on human serum albumin. Similar competition between bilirubin and gossypol occurs in the binding of these ligands to the glutathione S-transferases from human liver and placenta. In each case, gossypol and bilirubin exhibit similar binding constants. The binding properties of gossypol may generally mimic those of bilirubin.

Oral contraceptives: effect of long-term use on liver vitamin A storage assessed by the relative dose response test.

Vitamin A status measured by the relative dose response (RDR) test was determined among groups of Northern Thai women who had used estrogen-containing oral contraceptives (OCs) with or without multivitamin supplements through 13 cycles. Mean serum vitamin A values were elevated approximately 40% above those of control subjects (intrauterine contraceptive device (IUCD) users) during OC usage. Daily (one capsule) or periodic (two capsules 7 d/mo) multivitamin supplementation that included 1700 micrograms vitamin A per capsule did not significantly influence vitamin A serum values. The RDR test after 13 cycles was elevated in one individual who had taken OCs and the periodic multivitamin supplement. It reverted to normal after supplementation with vitamin A. A single high-dose vitamin A supplement (68,000 micrograms) did not change circulating levels of the vitamin. Among this population there is little evidence that use of estrogen-containing OCs for greater than 1 y resulted in a physiologically significant deterioration of vitamin A status.

PIP: Vitamin A status measured by the relative dose response (RDR) test was determined among groups of Northern Thai women who had used estrogen- containing oral contraceptives (OCs) with or without multivitamin supplements through 13 cycles. Mean serum vitamin A values were elevated approximately 40% above those of control subjects (IUD users) during OC usage. Daily (1 capsule) or periodic (2 capsules 7 days/month) multivitamin supplementation that included 1700 mcg vitamin A/capsule did not significantly influence vitamin A serum values. The RDR test after 13 cycles was elevated in 1 individual who had taken OCs and the periodic multivitamin supplement. It reverted to normal after supplementation with vitamin A. A single high-dose vitamin A supplement (68,000 mcg) did not change circulating levels of the vitamin. Among this population there is little evidence that use of estrogen-containing OCs for more than 1 year resulted in a physiologically significant deterioration of vitamin A status.

Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol.

Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans and has little liability for causing metabolic-based drug-drug interactions. In healthy women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent gabapentin administration did not alter the steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause contraceptive failure.

PIP: Anticonvulsants that induce hepatic metabolism increase the clearance of synthetic estrogens and progestogens used in oral contraceptives (OCs), thereby potentiating contraceptive failure. In contrast, the anticonvulsant drug gabapentin is not metabolized in humans and has little liability for metabolic-based drug interactions. The present study sought to confirm whether concurrent administration of gabapentin would alter the pharmacokinetics of norethindrone acetate (2.5 mg) and ethinyl estradiol (50 mcg) in healthy US women. A total of 13 women were enrolled for three menstrual cycles each. Pharmacokinetic values did not change appreciably as a result of the addition of gabapentin. The rate and extent of absorption of both hormones were unaffected by the anticonvulsant. Gabapentin plasma concentration time profiles and pharmacokinetic values from this study were similar to historical values after administration of gabapentin alone. The observed lack of interaction between gabapentin and norethindrone acetate or ethinyl estradiol is consistent with the fact that gabapentin is not metabolized, is not an inducer or inhibitor of hepatic drug metabolizing enzymes, is absorbed via a specific transport system for amino acids, and is not bound to plasma proteins. Anticonvulsant drugs that do not interact with OCs should be considered for the treatment of epileptic women of childbearing age who are using this method of fertility control.

Different effects of two progestins on plasma high density lipoprotein (HDL2) and postheparin plasma hepatic lipase activity.

Two progestins with different androgenic activity were compared for their effects on plasma high density lipoproteins and postheparin plasma lipase activities in premenopausal women. Levonorgestrel, a nortestosterone-derived steroid with androgenic activity reduced plasma HDL cholesterol by 17% (P less than 0.05) and HDL2 cholesterol by 30% (P less than 0.05), without changing the HDL3 cholesterol concentration. At the same time the postheparin plasma hepatic lipase activity was increased by 56% (P less than 0.01) whereas the lipoprotein lipase was not changed. None of these effects was reproduced during administration of medroxyprogesterone acetate, a progestin with low androgenic activity. The results suggest, first, that the decrease of HDL cholesterol observed during treatment with progestins is related to the androgenic activity of the steroid used, and, second, that the change in HDL (HDL2) is caused by androgen-induced increase of hepatic lipase activity.