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Biomedical subjects

G Fabre

Publications and source records attributed to G Fabre.

At least 19 recordsLinked to original sources
PubMed2005

[Breast reconstruction after prolonged tissue expansion. About 247 cases].

SUBJECT: The purpose of this study was to analyse the complications and the aesthetic results in case of slow tissue expansion in prosthetic breast reconstruction. PATIENTS AND METHODS: We tracked 237 patients representing 247 mammary reconstructions operated between 1992 and 2004. These patients were distributed in two series, a series of 148 operated mammary reconstructions between 1992 and 2000 and a series of 99 reconstructions operated between 2001 and 2004. For every reconstruction, we analysed the progress of the expansion, the complications and the quality of the aesthetic results according to the radiotherapy and the type of implant used. RESULTS: The radiotherapy increases the risk of failure of the breast reconstruction and degrades the quality of the aesthetic results. Capsular contractures are rare and their frequency does not depend on the irradiation. Prosthesis infections and exposure are more frequent on irradiated ground. DISCUSSION: The tissue expansion in prosthetic breast reconstruction is a technique studied well in the literature, but few authors use a chronic expansion and compare the long-term results according to the radiotherapy. If our study confirms the noxious role of the radiotherapy as for the complications and for the aesthetic aspect of the results, it is not a question for us of an absolute contraindication. The weak rate of capsular contracture is attributable to the chronic character of the expansion, which allows the maturation of the capsule. The use of silicone gel implants decreases the deflations but does not improve the results. CONCLUSIONS: The radiotherapy increases the risks of failure of the tissulaire expansion and decreases the quality of the aesthetic results. The chronic character of the expansion allows to obtain a rate of capsular contracture weak, even on irradiated ground. The silicone gel implants make it possible to obtain a perennial result.

Adult↗
PubMed2003

Target-controlled sedation-analgesia using propofol and remifentanil in women undergoing late termination of pregnancy.

Twenty-one women undergoing termination of pregnancy for severe fetal abnormality received remifentanil and propofol using a target-controlled infusion system and were studied prospectively. Target concentrations were initially set at 1 ng.mL(-1) for remifentanil and 0.8 microg.mL(-1) for propofol. Remifentanil concentration was adjusted to obtain visual analog scores <50 mm with preservation of ventilation. Visual analog scores assessed by the patients and physiologic data were recorded every 15 min until delivery. The median duration of administration was 150 min [10th-90th centiles: 42-282 min). Visual analog scores decreased within the first 5 min (P < 0.05) and remained under 50 mm for 91.7% of time. The median rate of infusion of remifentanil was 0.056 microg.kg(-1) min(-1) [10th-90th centiles: 0.037-0.15 ng.mL(-1)]. At delivery, the median target concentration was 2.2 ng.mL(-1) [10th-90th centiles: 1.25-4 ng.mL(-1)] for remifentanil and 0.8 microg.mL(-1) [10th-90th centiles: 0.32-1.12 microg.mL(-1)] for propofol. Remifentanil requirements were statistically correlated to gestational age, parity and duration of labor. No episodes of ventilatory depression, nausea, vomiting or pruritus were noted. Patients scored analgesia as excellent in 12 cases, good in 7 cases and moderate in 2 cases. Further studies are required to determine the place and the best regimen of remifentanil infusion for pain management in labor in those cases when epidural analgesia is contraindicated.

Journal Article↗
PubMed2002

Declared hepatitis C screening strategies in blood recipients in French hospitals.

AIMS OF THE STUDY: In spite of official recommendations and measures in France, screening strategies of hepatitis C performed in the field of transfusion are not clearly known. The aim of this study is to describe the screening strategies before and after the current year of the transfusion in blood recipients in several French medical departments and hospitals. MATERIALS AND METHODS: A qualitative study using the key informant technique was carried out. A sample of 179 departments and 64 hospitals in charge of patients transfused with low or high-volumes of homologous blood products was constituted. The key informants were asked about the number of homologous blood products, the number of recipients transfused in the hospital, the volume of transfusion performed, the existence of a single defined screening strategy, the time of prescription of the biological tests (before or after transfusion), the tests performed on cryopreserved blood samples, and the indications of the transfusion. RESULTS: The main screening strategy was HCV serology (second or third generation of enzyme immunoassays) with transaminase assessments before and after transfusion in 14% of the declared screening strategies. Screening tests were more frequently prescribed after transfusion, in at least 64% of the declared screening strategies according to the volume of transfusion. HCV serology was the common test prescribed in 61 and 50% of the screening strategies for low and high-volume transfusion respectively. The screening strategies showed a large heterogeneity combining HCV serology, transaminase assessment, before or after transfusion. CONCLUSION: A great heterogeneity of screening strategies was found. The most frequent was HCV serology with transaminase assessment before and after transfusion. Recommendations on screening strategies are needed in order to limit practice heterogeneity. This study will help building a cost-efficacy model in order to guide public health decision making.

Alanine Transaminase↗
PubMed2002

[Femoral shaft fractures in the elderly treated by intramedullary nailing].

PURPOSE OF THE STUDY: Little work has been devoted to femoral shaft fractures in the elderly, contrasting with the data available for proximal neck or trochanteric fractures. The purpose of this study was to determine the epidemiological and clinical features of femoral shaft fractures in the elderly from a retrospective series of 58 patients who underwent locked intramedullary nailing procedures with Grosse and Kempf (GK) or long gamma (GL) nails. MATERIAL AND METHODS: The series included 38 women and 20 men, mean age 83.6 years, who suffered a fracture of the femoral diaphysis due to a fall at home (49 fractures), a traffic accident (8 fractures) or a high-energy fall (1 fracture). Prior to the fracture, 10 patients had homolateral osteoarthritis and two had a contralateral hip arthroplasty. Twenty-six patients were in very good health, 19 had a history of cardiovascular disease, 9 had diabetes and 12 suffered parkinsonian syndromes or dementia. The ASA score was I in 24, II in 23 and III in 11. The diaphyseal fracture was isolated in 31 cases and associated with trochanteric involvement in 27. The upper third of the femur was involved in 37 cases, the middle third in 7 and the lower third in 14. Generally there was a simple spiroid subtrochanteric fracture line (36 cases), or a torsion wedge with or without a proximal extension. Mean delay to surgery was 1.9 days. Subtrochanteric fractures with a proximal line were stabilized with a GL (34 nails) and diaphyseal fractures with a GK (24 nails). Mean duration of the procedure was 1.9 for GL and 2 hours for GK. In 22 cases (17 GL and 5 GK), a minimally invasive access was needed to achieve reduction or stabilization during reaming and insertion of complementary fixation (3 screw fixations, 7 cerclages). RESULTS: Six patients died before six months, 4 during the initial hospitalization. Twenty patients experienced general complications: 7 cases of phlebitis and 5 "end-of-life" syndromes. Infection occurred in 3 cases including one septic arthritis leading to a bedridden situation. A new fracture beyond the ends of the implant occurred in 2 others. The upright position was achieved within 31 days and total weight bearing within 69 days. Bone fusion was achieved at 4 months (mean). Six patients died between 6 and 12 months, giving a 20.6% mortality at 1 year. Clinical outcome at 12 months was available for 42 living patients: 21 were walking without assistance, 7 used a cane, 8 required crutches or another assistance device and 6 were bedridden. DISCUSSION: The general and functional prognosis of femoral shaft fractures in the elderly is the same as for proximal fractures. These diaphyseal fractures can be individualized due to their characteristic mechanical and anatomic features: composite fracture with a rotation element involving the distal portion of the trochanter and the proximal quarter of the diaphysis. Several types of ostheosynthesis have been proposed for fixation. Locked intramedullary nailing has been found to be effective despite the difficulty in reduction, especially for particularly proximal fractures. There is a risk of iterative fracture in the transition zones between the femoral component and the osteoporotic bone.

Age Factors↗
PubMed2000

Expression and induction of CYP1A1/1A2, CYP2A6 and CYP3A4 in primary cultures of human hepatocytes: a 10-year follow-up.

1. The aims were to refine experimental conditions (using 76 human hepatocyte preparations) in terms of the selection of enzyme inducers and their optimal concentration, the treatment duration with inducers and the choice of specific cytochrome P450 isoform(s) probes to optimize the use of primary hepatocytes for predicting the potential induction by new chemical entities of cytochrome P450 isoforms in vivo in man. 2. In the absence of any inducer, basal cytochrome P450 isoform(s)-mediated activities decreased to 20% of their initial activity (end of the seeding period) by 72-96 h. In contrast, UGT-dependent enzyme activities remained at a constant level (+/- 20%) up to the fifth day of culture. 3. Beta-naphthoflavone, at an optimal concentration of 50 microM and after a 3-day treatment, specifically and potently induced 7-ethoxyresorufin (10.4 +/- 10.4-fold, n = 74) and phenacetin (6.6 +/- 6.4-fold, n = 60) O-deethylation processes, markers for CYP1A1 and CYP1A2 isoforms respectively. Only a 2-fold increase was noted following treatment with 2 mM phenobarbitone, whereas dexamethasone and rifampicin had no effect at all. 4. A 3-day treatment of human hepatocytes with 50 microM dexamethasone was associated with a major induction of both coumarin 7-hydroxylation (9.4 +/- 11.4-fold, n = 49) and nifedipine dehydrogenation (4.7 +/- 3.8-fold, n = 61), markers for CYP2A6 and CYP3A4 respectively. Phenobarbitone, however, exhibited a broad but moderate inducing effect on 7-ethoxyresorufin (2.2 +/- 1.5-fold, n = 55) and phenacetin (1.7 +/- 0.9-fold, n = 54) O-deethylation, coumarin 7-hydroxylation (3.9 +/- 9.2-fold, n = 50) and nifedipine dehydrogenation (2.1 +/- 2.0-fold, n = 47). 5. Km obtained for the different cytochrome P450 isoform substrates in untreated hepatocytes were in the same range of magnitude that those determined on human hepatic microsomal fractions. Enzyme induction processes were characterized by a large increase in apparent Vmax whereas apparent Km were not affected. 6. These studies demonstrate that human hepatocytes in primary culture can respond specifically and quantitatively to model inducers. This in vitro system offers a useful approach to study the regulation of human hepatic biotransformation activities and should facilitate the demand for a reproducible method for addressing cytochrome P450 induction.

Adult↗
PubMed1999

[Fall in the seroprevalence of hepatitis A in French youth].

OBJECTIVE: An anti-hepatitis A virus seroprevalence survey was performed in 1997 in 1052 French army recruits (mean age: 21.2 years). To describe epidemiological trends, the current pattern was compared to previous results obtained by similar methods in 1985, 1990 and 1993. RESULTS: In 1997, overall anti-hepatitis A virus seroprevalence was 11.5%. The greatest risk factor of hepatitis A infection was related to travel in intermediate or highly endemic areas for hepatitis A virus: 46% of overseas residents (odds ratio = 10.3), 28% of recruits who had travelled in developing countries (odds ratio = 3.7) and 7.65% of French living in industrialised countries are anti-hepatitis A virus antibody positive. Moreover, seroprevalence was higher in subjects with a history of icteria (adjusted odds ratio = 3.5) and families with at least 3 children (adjusted odds ratio = 3). No association was found with drinking water, socioeconomic status such as baccalaureat degree, or parents profession. The seroepidemiological shift of hepatitis A, as assessed in three previous studies, shows a marked decrease of 20% in 12 years from 30.4% in 1985, to 21.3% in 1990, to 16.3% in 1993, and to 11.5% in 1997. The decrease in the prevalence of anti-hepatitis A virus was more marked in young adults who had never travelled in endemic countries (decrease of 20%) than those who had visited or lived in developing countries (decrease of 10%). CONCLUSION: Although France is not highly endemic for hepatitis A thanks to improved hygiene and housing conditions over the past 20 years, a pattern of intermediate endemicity was seen in French overseas areas in which the risk of outbreaks of hepatitis A was higher. The decrease in anti-hepatitis A virus seroprevalence in French youth can be used to draft a public health policy for hepatitis A control.

Adolescent↗
PubMed1999

Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes.

The oxidative metabolism of irbesartan, a new nonpeptide angiotensin II receptor antagonist, was investigated on 12 human fully characterized hepatic microsomes and purified cytochrome P-450 (CYP) isoforms. After incubation of microsomes with irbesartan and NADPH, four main hydroxy metabolites were formed, as confirmed by liquid chromatography-mass spectrometry analysis. Irbesartan oxidation follows Michaelis-Menten kinetics, consistent with the involvement of a single CYP isoform in these hydroxylation processes. Only a low interindividual variability (2-fold difference) was observed in drug oxidation, even in preparations lacking CYP2D6. Km and Vmax for irbesartan oxidation were 54 +/- 6.5 microM and 0.62 +/- 0.18 nmol/min/mg, respectively. Irbesartan oxidation correlated (r2 = 0. 769) with tolbutamide (CYP2C9 substrate) 4-methyl-hydroxylation. Oxidation of irbesartan was markedly inhibited by sulfaphenazole (CYP2C9 inhibitor), but not by any of several other CYP inhibitors. In the same manner, both tolbutamide and warfarin (CYP2C9 substrates), were competitive-type inhibitors of irbesartan oxidation with Ki values of 500 and 30 microM, respectively. Moreover, irbesartan was a competitive-type inhibitor of tolbutamide 4-methylhydroxylation (Ki = 317 microM). Nifedipine also potentially decreased irbesartan oxidation, whereas neither ketoconazole and triacetyloleandomycin (CYP3A inhibitors), nor diltiazem and verapamil, (CYP3A4 substrates), exhibited an inhibitory effect. Additional studies demonstrated that nifedipine was an inhibitor of irbesartan (Ki = 20 microM) and tolbutamide oxidation processes, whereas irbesartan had no effect at all on nifedipine dehydrogenation. Enzyme kinetics suggest that nifedipine is a noncompetitive-type inhibitor of CYP2C9-mediated catalytic activities. Finally, only microsomes containing recombinant human liver CYP2C9 were capable of oxidizing irbesartan. These results provide evidence that CYP2C9 plays a major role in irbesartan oxidation.

Adult↗
PubMed1998

Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line.

PURPOSE: To determine and compare the relationship between in vivo oral absorption in humans and the apparent permeability coefficients (Papp) obtained in vitro on two human intestinal epithelial cell lines, the parental Caco-2 and the TC-7 clone. METHODS: Both cell lines were grown for 5-35 days on tissue culture-treated inserts. Cell monolayers were analysed for their morphology by transmission electron micrography, and for their integrity with respect to transepithelial electrical resistance, mannitol and PEG-4000 transport, and cyclosporin efflux. Papp were determined for 20 compounds exhibiting large differences in chemical structure, molecular weight, transport mechanisms, and percentage of absorption in humans. RESULTS: The TC-7 clone exhibits morphological characteristics similar to those of the parental Caco-2 cell line, concerning apical brush border, microvilli, tight junctions and polarisation of the cell line. The TC-7 clone however appeared more homogenous in terms of cell size. Both cell lines achieved a similar monolayer integrity towards mannitol and PEG-4000. Monolayer integrity was achieved earlier for the TC-7 clone, mainly due to its shorter doubling time, i.e. 26 versus 30 hours for parental Caco-2 cells. When using cyclosporin A as a P-glycoprotein substrate, active efflux was lower in the TC-7 clone than in the parental Caco-2 cells. The Papp and mechanisms of transport (paracellular or transcellular routes, passive diffusion and active transport) were determined for 20 drugs. A relationship was established between the in vivo oral absorption in humans and Papp values, allowing to determine a threshold value for Papp of 2 10(-6) cm/sec, above for which a 100% oral absorption could be expected in humans. Both correlation curves obtained with the two cell types, were almost completely superimposable. These studies also confirmed that the dipeptide transporter is underexpressed in both cell lines. CONCLUSIONS: On the basis of morphological parameters, biochemical activity and drug transport characteristics, the TC-7 clone appeared to be a valuable alternative to the use of parental Caco-2 cells for drug absorption studies.

Administration, Oral↗
PubMed1997

[Consequences for labile blood products of leukocyte depletion by whole blood filtration using the Leucoflex LST1 in-line filter. Evaluation of the Leucoflex LST1 filter].

The aim of this study is to evaluate the effects of whole blood filtration after a storage time of 20-24 hours at laboratory temperature using the in line filter Leucoflex LST1. The study concerns 49 blood donations in which we studied leukocyte depletion, proteins (IgG, IgA, IgM, haptoglobin, C3, C4), coagulation factors (fibrinogen, factors XII, XI, IX, VIII, V, proteins S and C, plasminogen, tPA, D-Dimers, PDF) at day 1, the parameters of conservation (ATP, 2-3 DPG, extra cellular potassium, haemolysis, pH) of red blood cell concentrates (RCCs) and bacteriological sterility at day 1 and 42. Despite a correct leukocyte depletion (mean depletion of 3.96 log), a 10 fold higher mean level of residual leukocytes/unit than with buffy coat poor RCC filtration (0.514.10(6) vs 0.051.10(6)) is observed. Moreover a lot of concentrates are not in accordance with French regulations (7/42 with more than 1.10(6) leukocytes/unit). The variation of the rates of IgG, IgA, IgM, haptoglobin, C4 and protein C is not significant. For the others there is a slight decrease with a mean level remaining in a physiological range. No sign of activation is noted. The sterility assays remain negative and the RCC conservation is not altered. In conclusion, even if the quality of the leukocyte depletion is not satisfactory in our study and has to be stated more precisely by multicenter studies, the whole blood filtration does not alter the quality of the derived components and allows us obtain RCC in a bigger volume and containing more haemoglobin than with the classical procedure after removing the buffy-coat [10].

Blood↗
PubMed1996

Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes.

Cytochrome P450 chemical inhibitors are widely used to define the role of individual cytochrome P450 isozyme(s) in a metabolism process. In this study, cytochrome P450 isoform-dependent reactions were investigated on our human liver microsomes bank (n = 34) and characterized for both KM and VMAX values (n > or = 3). These metabolic reactions were: 7-ethoxyresorufin O-deethylation (CYP1A1), phenacetin O-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), tolbutamide 4-methylhydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), aniline 4-hydroxylation (CYP2E1) and nifedipine dehydrogenation (CYP3A4). Literature data-based specific inhibitors were selected and characterized for both their inhibitory constant (Ki) and the inhibition-type toward their specific substrate. Results were as follows: alpha-naphthoflavone (CYP1A1; mixed-type interaction with a Ki = 0.01 microM), furafylline (CYP1A2; competitive-type interaction with a Ki = 3 microM when microsomes were incubated with both furafylline and phenacetin; noncompetitive-type interaction with a Ki = 0.6 microM when microsomes were preincubated with furafylline and NADPH), pilocarpine (CYP2A6; competitive-type interaction with a Ki = 4 microM), sulfaphenazole (CYP2C9; competitive-type interaction with a Ki = 0.3 microM), quinidine (CYP2D6; competitive-type interaction with a Ki = 0.4 microM, diallyldisulfide (CYP2E1; noncompetitive-type interaction with a Ki = 150 microM on an aniline concentration range of 10-60 microM; competitive-type interaction with a Ki = 100 microM on an aniline concentration range of 80-2000 microM) and ketoconazole (CYP3A4; mixed-type interaction with a Ki = 0.015 microM). Once the inhibitors' potency was determined, the selective effects of these inhibitors were evaluated after incubation of human hepatic microsomes with isoform-selective substrates in the presence of the different chemical inhibitors. Up to 10 times the Ki value toward the isoform-selective probe, pilocarpine, sulfaphenazole, quinidine and ketoconazole exhibited potent inhibitory and specific effects. alpha-Naphthoflavone and furafylline both inhibited phenacetin and 7-ethoxyresorufin O-deethylation processes, a consequence of the absence of CYP1A1 in noninduced human liver. Diallyldisulfide exhibited broad and nonspecific inhibitory effects. When used in their "window of selectivity," ie., up to 10-fold the Ki value, most chemical inhibitors powerfully and specifically inhibited cytochrome P450 isoform-specific reactions when analyzed at their KM values.

Adult↗
PubMed1995

The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications.

The gastrointestinal tract remains the most popular and acceptable route of administration for drugs. It offers the great advantage of convenience and many compounds are well absorbed and thereby provide acceptable plasma concentration-time profiles. Currently there is considerable interest from the pharmaceutical industry in development of cell culture systems that would mimic the intestinal mucosa in order to evaluate strategies for investigating and/or enhancing drug absorption. The intestinal epithelial cells of primary interest, from the standpoint of drug absorption and metabolism, are the villus cells, which are fully differentiated cells. An in vitro cell culture system consisting of a monolayer of viable, polarized and fully differentiated villus cells, similar to that found in the small intestine, would be a valuable tool in the study of drug and nutrient transport and metabolism. The Caco-2 cell line, which exhibits a well-differentiated brush border on the apical surface and tight junctions, and expresses typical small-intestinal microvillus hydrolases and nutrient transporters, has proven to be the most popular in vitro model (a) to rapidly assess the cellular permeability of potential drug candidates, (b) to elucidate pathways of drug transport (e.g., passive versus carrier mediated), (c) to assess formulation strategies designed to enhance membrane permeability, (d) to determine the optimal physicochemical characteristics for passive diffusion of drugs, and (e) to assess potential toxic effects of drug candidates or formulation components on this biological barrier. Since differentiated Caco-2 cells express various cytochrome P450 isoforms and phase II enzymes such as UDP-glucuronosyltransferases, sulfotransferases and glutathione-S-transferases, this model could also allow the study of presystemic drug metabolism.

Caco-2 Cells↗
PubMed1995

Risk factors for hepatitis A infection in France: drinking tap water may be of importance.

The prevalence of serologic markers for hepatitis A was investigated in 936 French male military recruits from October 1992 to June 1993. Data were collected in order to assess the evolution of seroprevalence level according to the decline observed for several years and to appreciate the importance of potential risk factors. The overall prevalence of antibody against hepatitis A virus was 16.3%. The prevalence was higher among those with high number of siblings and whose Father's occupation falls into low professional class categories. Multivariate analysis found that high level of seroprevalence was also associated with tap water consumption (odd ratio (OR) = 1.56; p < 0.04), overseas travels (OR = 2.26; p < 0.001) and was higher for recruits reporting an history of clinical jaundice (OR = 2.27; p < 0.01). Together with more anticipated factors, tap water consumption may be of importance in France and this study points out the potential part taken by chlorinated water.

Adolescent↗
PubMed1995

Properties of red blood cell concentrates stored in PAGGS-sorbitol.

The physiological, biochemical, morphological and rheological characteristics of RBC resuspended in PAGGS-Sorbitol were studied over, and beyond, 49 days. The levels of P50 and 2,3-DPG, as well as the concentration of ATP, stayed above acceptable values for longer periods than those described with other Optional Additive Solutions (OAS). Spontaneous hemolysis was kept below 1%, cell morphology, viscosity, deformability and other factors such as pH, the ratio of glucose consumption to lactate formation, the total adenylates and energetic charge indicate that good properties should be seen after 49 days' storage. In vivo survival studies using a double isotope technique showed that at least 75% of those RBC stored in this OAS for 49 days were still in circulation 24 hours after injection. Therefore RBC stored in PAGGS-S can be kept for 49 days with excellent in vivo survival, as well as maintaining DPG levels for up to 3 weeks. Furthermore, a clinical trial in routine conditions for use has been carried out with surgical and medical patients as well as with hemodialysed patients. The results obtained are those that could at least be expected of normal stored blood. As regards RBC/PAGGS-Sorbitol, it would be reasonable to propose a storage period of 49 days in the liquid state.

Adenine↗
PubMed1994

In vitro N-glucuronidation of SB 47436 (BMS 186295), a new AT1 nonpeptide angiotensin II receptor antagonist, by rat, monkey and human hepatic microsomal fractions.

The glucuronidation of the AT1 nonpeptide angiotensin II receptor antagonist, SR 47436 (BMS 186295), was investigated in hepatic microsomes prepared from various species, i.e., Sprague-Dawley rat, Cynomolgus monkey and Caucasian humans. The drug was found to undergo N-glucuronidation on the tetrazole moiety as confirmed by its hydrolysis by beta-glucuronidase, its associated radioactivity when UDP-[U-14C]glucuronic acid was used as substrate and by different techniques such as high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. Glucuronide formation was optimal at pH 5.0 along with a "0.2 mg of Brij 58 per mg of protein" ratio, regardless of the investigated species. Cynomolgus monkey microsomes glucuronidated SR 47436 (BMS 186295) to the greatest extent, with a relative catalytic efficiency 11.0- and 2.6-fold higher than that observed in rat and human, respectively. SR 47436 (BMS 186295) glucuronidation followed Michaelis-Menten kinetics. Bilirubin:UDP-glucuronosyltransferase isoform was not involved, inasmuch as bilirubin did not affect its glucuronidation, 7,7,7-triphenylheptanoic acid was a noncompetitive inhibitor and glucuronidation was only decreased 2-fold in Gunn rats. SR 47436 (BMS 186295) glucuronidation was enhanced markedly after treatment of rats with dexamethasone (Vmax/Km = 71.5 vs. 2.6 in untreated animals). Among the drugs used which undergo phenolic, carboxylic acid, alcohol or tertiary amine glucuronidation, only monodigitoxigenin-monodigitoxoside, flurbiprofen, naproxen, testosterone and estrone inhibited SR 47436 (BMS 186295) glucoronidation in a noncompetitive manner. These data suggest that SR 47436 (BMS 186295) was glucuronidated by a highly dexamethasone-inducible UDP-glucuronosyltransferase isoform(s), different from that involved in the glucuronidation of monodigitoxigenin-monodigitoxoside.

Angiotensin II↗