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Biomedical subjects

D Carlhant

Publications and source records attributed to D Carlhant.

15 recordsLinked to original sources
PubMed1998

Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors.

Ritonavir, indinavir, and saquinavir, all human immunodeficiency virus-1 protease inhibitors with a potent antiviral effect during triple therapy, are extensively metabolized by liver cytochrome P450 3A4. As this P450 isoform is involved in the metabolism of about 50% of drugs, coadministration of protease inhibitors with other drugs may lead to serious effects due to enzyme inhibition. Among these drugs, methadone and buprenorphine, both metabolized by P450 3A4, are potential candidates to drug interactions. In this study, metabolic interactions between these protease inhibitors and methadone or buprenorphine were studied in vitro in a panel of 13 human liver microsomes. Ritonavir was the most potent competitive inhibitor with Ki about 50 and 20 nM for methadone and buprenorphine metabolisms, respectively. Indinavir and saquinavir also inhibited methadone N-demethylation (Ki about 3 and 15 microM, respectively) and buprenorphine N-dealkylation (Ki about 0.8 and 7 microM, respectively). The rank order of inhibition potency against metabolism of methadone and buprenorphine was ritonavir > indinavir > saquinavir. There is obvious potential for clinically significant drug interactions, particularly with ritonavir. In brief, caution should be advised if human immunodeficiency virus-1 protease inhibitors are coadministered with methadone and buprenorphine.

Alkylation↗
PubMed1994

Four-week treatment with omeprazole increases the metabolism of caffeine.

OBJECTIVES: It has been suggested that omeprazole is an inducer of the cytochrome P450 1A, both in vitro and in vivo. To evaluate whether omeprazole treatment might affect the activity of P450 1A2, we performed a study of caffeine metabolism, which is mainly via P450 1A. METHODS: Thirteen subjects (one healthy volunteer and 12 patients) who were treated with omeprazole, 20 mg each morning for 4 wk, and a control group of 13 healthy volunteers, participated in the study. A test of caffeine metabolism was performed before treatment, 28 days after beginning treatment and, whenever possible, 28 days after treatment. Blood samples were analyzed for theobromine, paraxanthine, and theophylline, by high performance liquid chromatography. RESULTS: P4501A2 activity was determined as the ratio of (paraxanthine + theobromine + theophylline)/(metabolites + caffeine) which represents the total caffeine N-oxidative demethylations; this ratio was expressed as a percentage. For patients, on day 0, the percentage of total metabolism was 34.3% +/- 8.3; on day 28, it was 42.7% +/- 10.8; the difference was statistically significant (p < 0.01). No intra-individual variation of P450 1A2 activity was observed in the control group. CONCLUSIONS: These results demonstrate that omeprazole increases the metabolism of caffeine, especially N-1 and N-3 demethylation pathways, after 28 days of treatment with omeprazole, and suggest that omeprazole, when used for this period, is an inducer of hepatic cytochrome P4501A2.

Caffeine↗
PubMed1991

Metabolism of doxorubicin, daunorubicin and epirubicin in human and rat hepatoma cells.

The metabolism of three anthracyclines, namely daunorubicin, doxorubicin and epirubicin, was studied in two human (HepG2 and HBG2) and one rat (FAO) hepatoma cell lines. Both species and substrate differences in anthracycline metabolism were retained by these hepatoma cell lines with regard to the aldoketoreductase pathway. However, glucuronidation of epirubicin normally found in vivo and in human hepatocyte cultures was not recovered in human hepatoma cells, further indicating that these cells express only some of the liver functions. Nevertheless, these cell lines could be a suitable model to investigate the still poorly understood aldoketoreductase activity.

Animals↗
PubMed1989

Solid phase extraction and HPLC determination of spiramycin in plasma and vitreous concentrations.

A method for extracting spiramycin by an octadecylsilica cartridge is described for plasma or vitreous samples. The macrolide antibiotic is then measured by reversed-phase HPLC with UV detection. The limit of detection is estimated to be 50 ng/mL. The coefficient of variation for the procedure is 6.1% and 5.2% for the range of concentrations 0.2 micrograms/mL and 10 micrograms/mL respectively. By this method, pharmacokinetic profiles were performed for five adult patients. Spiramycin could be accurately measured in the vitreous humour, allowing the determination of antibiotic at its site of action.

Chromatography, High Pressure Liquid↗
PubMed1988

Caffeine and theophylline metabolism in newborn and adult human hepatocytes; comparison with adult rat hepatocytes.

Cultured hepatocytes from newborn human (three samples), adult human (eight samples) and adult rat livers were used to study the metabolism of theophylline and caffeine, two drugs of which the metabolic pathways are known to be cytochrome P-450-dependent. Known metabolic pathways of caffeine in vivo were qualitatively maintained. However, only the primary metabolites were formed through oxidative N-demethylation giving theophylline, paraxanthine and theobromine and, through C-8 hydroxylation, giving 1,3,7-trimethyluric acid and a ring-opened compound the 6-amino-5[N-formylmethylamino]1,3-dimethyl uracil. The ratio of the three dimethylxanthine metabolites was dependent upon the species (human, rat), development stage (newborn, adult) and environmental factors. Similarly, theophylline was metabolized as in vivo by the demethylation pathway giving, preferentially, 3-methylxanthine and not 1-methylxanthine, and by a C-8 oxidation giving 1,3-dimethyluric acid. In newborn hepatocytes, all pathways were absent except the well-known methylation to caffeine. Moreover, such a methylation also occurred in adult human hepatocytes. This result was explained by the very low metabolic capacity of cultured cells, allowing the detection of only direct metabolites. Indeed, the overall biotransformation of both the methylxanthines by primary cultures of hepatocytes was remarkably weak, confirming previous studies with liver microsomal incubations. Thus the metabolism rate did not exceed about 30 nmoles/10(6) cells/24 hr in human adults, except for two subjects which were characterized by an extensive metabolism and a different metabolic profile. These two subjects were probably induced in vivo by environmental compounds. Both quantitative and qualitative data obtained from this study were roughly correlated with other in vivo and in vitro studies. Overall the experimental model of cultured human hepatocytes was shown to be capable of assessing the metabolic profile of two methylxanthines which is in agreement with the situation encountered in vivo. This example suggests that a breakthrough may be brought in new drugs development by the predictability from human hepatocyte culture model to the in vivo human situation.

Adult↗
PubMed1988

[Neonatal hemolytic anemia after intra-amniotic injection of methylene blue].

The authors report two cases of neonatal hemolytic anemia without methemoglobinemia secondary to intraamniotic injection of 10 mg of methylene blue. Evolution was favourable without exchange transfusion. This emphasizes the importance of searching for a toxic origin in case of neonatal hemolytic anemia without apparent cause.

Adolescent↗
PubMedDate not supplied

[Contribution of in vitro models to the management of hematologic risk in pharmacovigilance].

The decisions of health authorities concerning adverse effects of drugs are usually notified following clinical observations, but are rarely associated to experimental data. The haematopoietic tissue is one of the most sensitive to these effects. In order to anticipate and to explain adverse effects, it becomes necessary to carry out in vitro assays on normal human haematopoietic progenitors. We had the opportunity to use human cord blood progenitors which are able to repopulate allogeneic aplastic bone marrow. Many advantages are associated with this model: numerous samples, non-invasive, absence of species bias, possibilities of mechanistic approach. The clonogenic potential of progenitors in soft agar, as well as their ability to expand in liquid medium after stimulation with specific growth factors, have been used. Evidence of dose-related toxicity by inhibition of colony formation or proliferation was analysed in the presence of reference molecules. Results were reproducible despite an intrinsic variability of progenitor density between samples. They were comparable to assays on bone marrow progenitors reported by us and others. Comparison of toxicity thresholds with plasma therapeutic ranges showed the potential risk for some molecules tested.

Animals↗