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M A Sarkar

Publications and source records attributed to M A Sarkar.

At least 19 recordsLinked to original sources
PubMed2002

Characterization of quinidine 3-hydroxylation as a probe for the CYP 3A enzyme using a novel capillary electrophoresis technique.

Capillary electrophoresis (CE) with a direct injection technique was used to characterize the formation of (3S)-3-hydroxyquinidine (3-OHQ) as a probe for the CYP 3A isoenzymes in rat liver microsomes. Detection was performed either in the absorbance mode or by employing laser-induced fluorescence (LIF) detection. Michaelis-Menten parameters (mean values+/-S.D.) K(m) and V(max) for the formation of 3-OHQ from the probe drug quinidine sulfate (QS) in rat liver microsomes were 37+/-4.6 micro g/ml (47.1+/-5.9 micro M) and 321+/-4 ng/mg/h (942+/-11.7 pmol/mg/h), respectively. Inhibition studies were performed to evaluate the specificity of 3-OHQ as a probe for the CYP 3A enzyme. Ketoconazole and fluconazole were found to be inhibitors of 3-OHQ formation and exhibited K(i) values of 0.19 and 20.1 micro M, respectively. Inhibition with the weak inhibitor, erythromycin could only be estimated using LIF detection due to lack of sensitivity in the absorbance mode. The formation of 3-OHQ in rat liver microsomes can be used as a model for the screening of the CYP 3A enzyme. Direct injection, ensures faster analysis time due to the lack of sample preparation and the low volume capabilities of the technique makes it attractive for the screening of a large number of compounds.

Animals↗
PubMed2002

Irreversible inhibition of CYP2D6 by (-)-chloroephedrine, a possible impurity in methamphetamine.

(+)- and (-)-Chloroephedrine, and their respective aziridines, cis- and trans-1,2-dimethyl-3-phenylaziridine, have been reported present in clandestinely synthesized methamphetamine. Since methamphetamine and structurally related compounds are potential substrates for human liver CYP2D6, the possible interaction of the chloroephedrines with human liver CYP2D6 was evaluated. Computational methods (using Flexidock and HINT in SYBYL) were used to determine the feasibility of (+)- or (-)-chloroephedrine and cis- or trans-1,2-dimethyl-3-phenylaziridine binding in the active site of a three dimensional CYP2D6 molecular model. Although modeling indicates both (+)- and (-)-chloroephedrine would bind comparably to methamphetamine, the binding energies of cis- or trans-1,2-dimethyl-3-phenylaziridine products indicate a preference for trans-1,2-dimethyl-3-phenylaziridine, the product formed from (-)-chloroephedrine. The effects of (+)- and (-)-chloroephedrine on the metabolism of dextromethorphan in human liver microsomes were then experimentally evaluated. (+)-Chloroephedrine (50 micro M) had no effect on human CYP2D6. (-)-Chloroephedrine appeared to be selective for human CYP2D6 versus CYP1A2 and CYP3A4/5. The inhibition of CYP2D6 was time-dependent, not dependent on metabolic activation, and irreversible. It appeared to bind at the active site of CYP2D6 with an apparent K(i) of 226 micro M, with a k(int) of 0.039 min(-1), and a t(1/2) of 23 min. Due to the irreversible nature of this inhibition, this impurity in clandestinely synthesized methamphetamine may be important and warrant further study.

Cytochrome P-450 CYP2D6↗
PubMed2001

Persistence and metabolism of imidacloprid in different soils of West Bengal.

A laboratory experiment was performed to study the persistence of imidacloprid from two formulations (Confidor 200 g litre-1 SL and Gaucho 700 g kg-1 WS), and its metabolism in three different soils (Gangetic alluvial soil of Kalyani, lateritic soil of Jhargram and coastal alkaline soil of Canning) of West Bengal following application at 0.5 kg and 1.0 kg AIha-1. Dissipation of imidacloprid in soil followed first-order kinetics and DT50 values ranged from 28.7 to 47.8 days. The shortest half-lives (28.7 and 35.8 days) were observed in the lateritic soil of Jhargram for both liquid and powder formulations. The formation of two metabolites of imidacloprid, imidacloprid-urea and imidacloprid-olefin, was first detected on day 30 of degradation at 28 (+/- 1) degrees C in all three soils.

Environment, Controlled↗
PubMed2001

Linear and knemometric growth in the early phase of rehabilitation from severe malnutrition.

The relationship between ponderal, linear and lower leg growth in children recovering from severe malnutrition remains unclear. We report on the early growth of 141 severely malnourished Bangladeshi children aged 6 to 36 months of age who were followed for 90 d. Mean (sd) weight for height (WHZ) and height for age (HAZ) catch-up growth z scores over the 90 d were 1.6 (0.85) and 0.47 (0.325) respectively. Mean (sd) lower leg length growth was 10.35 (4.5) mm. Change in HAZ was significantly associated with initial WHZ, but linear growth occurred in the presence of severe wasting and no threshold WHZ score was identified. Lower leg length gain correlated throughout with ponderal indices but with change in HAZ score only after day 45. Only initial WHZ score and maternal height predicted for linear growth and only accounted for 20 % of total variance. We conclude that linear growth occurs early in severely malnourished children but that knemometry behaves as a ponderal index acutely.

Anthropometry↗
PubMed1999

Glutathione S-transferase in human endometrium: quantitation and interindividual variability in isoform content.

OBJECTIVES: The goals of the present study were to determine whether human endometrium contains glutathione S-transferases (GSTs), to identify the isoforms present (if any) and to assess the causes of any intersubject variability which was observed. METHOD: Hysterectomy patients (n = 32, 13 with endometrial carcinoma) were examined in the core study. The ability of cytosol from these endometria to conjugate 1-chloro-2,4-dinitrobenzene was measured. Additional studies with chemical inhibitors and monoclonal antibodies to GSTpi were also performed. RESULTS: The pattern of inhibition caused by ethacrynic acid and cibacron blue strongly suggests substantial interindividual variability in type (alpha and pi dominant) and amount ( approximately 10-fold) of this important group of enzymes. Significantly lower GST activity was seen in cancer patients who were smokers when compared with all other subjects (p < 0.05). CONCLUSION: There are substantial interindividual differences in the GST content of human endometrium. Furthermore, lower GST activity in tissues from endometrial carcinoma patients with a history of smoking may have contributed to the neoplastic transformation of this tissue.

Cytosol↗
PubMed1999

Pharmacodynamic profile of prolonged etoposide administration in patients with small cell lung cancer and non-Hodgkin's lymphoma.

STUDY OBJECTIVE: To determine whether therapeutic drug monitoring can enhance administration of etoposide in patients with drug-responsive neoplasms. DESIGN: Prospective, open-label study. SETTING: University-affiliated hospital and cancer center. PATIENTS: Sixteen patients with small cell lung cancer or low-grade non-Hodgkin's lymphoma. INTERVENTIONS: Patients were treated with etoposide, 25 mg/m2/day over 24 hours by continuous infusion for 35 days. Peripheral blood samples were collected twice a week to measure etoposide levels. Plasma was separated, frozen and stored at -20 degrees C until assayed. MEASUREMENTS AND MAIN RESULTS: Steady-state plasma etoposide concentrations (ECpss) were determined and used to calculate total systemic clearance (Clsys). Despite differences in dosage and administration schedules, etoposide Clsys was similar to previous reports. In addition, a biexponential relationship between ECpss and absolute neutrophil count was demonstrated by nonlinear least squares estimation. Values generated from this equation indicated that ECpss above 1.5 microg/ml was strongly associated with grade III-IV leukocyte toxicity. Although less precise, there may also be a correlation between ECpss and antitumor activity. CONCLUSION: Based on these findings, we propose a pharmacodynamic construct that uses measurements of both pharmacokinetic (ECpss, Clsys) and pharmacodynamic (hematologic toxicity, tumor response) parameters for patients with etoposide-sensitive tumors. Therapeutic drug monitoring may be able to mitigate hematologic toxicity.

Adult↗
PubMed1998

Regiospecific expression of cytochrome P4501A1 and 1B1 in human uterine tissue.

The goal of this study was to investigate the expression of these isoforms in different regions of the human uterus. Expression was determined in the endometrium (ENDO), endocervix (CERV) and squamous region (SR) from six non-smoking women by using RT-PCR. The transcripts encoding for CYP1A1 were significantly higher (P < 0.05) in the SR compared to the other areas. However, the expression of CYP1B1 was significantly higher (P < 0.05) in the ENDO. CYP1B1 expression appeared to be extremely low in a woman in the secretory stage of the menstrual phase, relative to the ENDO of the other patients who were all in the proliferative stage at hysterectomy. CYP1B1 mRNA was expressed in only two out of six patients in the SR and in three out of five patients in the CERV. CYP1A1 was also uniformly expressed in the ENDO of all except one patient, whereas expression was minimal in the other regions. It is likely that variability in the expression of these isoforms may be responsible for the differential susceptibility to cancer in women.

Adult↗
PubMed1998

Pharmacokinetics of minoxidil in patients with cirrhosis and healthy volunteers.

OBJECTIVES: To determine the effect of reduced hepatic function on the pharmacokinetics of minoxidil. The pharmacokinetics of antipyrine, lorazepam, and indocyanine green were included as indicators of hepatic function. METHODS: Eight mild cirrhotics and eight healthy subjects received antipyrine (po), lorazepam (IV), indocyanine green (IV) and minoxidil 5 mg (po). Blood and urine were sampled for up to 72 h after each drug, and drug concentrations were measured by validated HPLC methods. Blood pressure and heart rate were measured for safety. RESULTS: For unchanged minoxidil, the serum elimination rate constant was significantly smaller and mean residence time was significantly longer in cirrhotic patients. Urinary elimination rate constant for minoxidil glucuronide was significantly smaller and fraction of dose excreted in urine was significantly higher in cirrhotic patients. Antipyrine elimination was significantly slower for cirrhotic patients. No differences were observed in lorazepam pharmacokinetic parameters. CONCLUSION: Pharmacokinetic analysis suggests a longer dosage interval may be appropriate in patients with hepatic impairment. In the absence of multiple-dose minoxidil pharmacodynamic studies in this population, minoxidil should be used as in other populations: begin with a modest dose, and adjust the dose based on clinical response.

Adult↗
PubMed1998

Zinc and rehabilitation from severe protein-energy malnutrition: higher-dose regimens are associated with increased mortality.

A randomized, double-blind trial was undertaken to measure the effects of zinc supplementation on catch-up growth in severe protein-energy malnutrition, with particular reference to linear growth. One hundred forty-one children between the ages of 6 mo and 3 y were enrolled after admission to a nutritional rehabilitation unit in Dhaka, Bangladesh, and randomly assigned to receive elemental zinc by mouth, 1.5 mg/kg for 15 d, 6.0 mg/kg for 15 d, or 6.0 mg/kg for 30 d, and thereafter they were followed for a total of 90 d. Anthropometric outcome measures included change in knee-heel length, midupper arm circumference, subscapular and triceps skinfold thicknesses, and change in height-for-age, weight-for-age, and weight-for-height z scores. Higher zinc doses were not associated with significant change in any anthropometric measurement, but mortality was significantly greater in children who received high-dose zinc (6.0 mg/kg) initially as opposed to those who received low-dose zinc supplementation (1.5 mg/kg) (Yates-corrected chi-square P value of 0.033 and a risk ratio of 4.53; 95% CI: 1.09 < risk ratio < 18.8). We conclude that there is no benefit to using high-dose zinc supplementation regimens and that they could contribute to increased mortality in severely malnourished children.

Anthropometry↗
PubMed1994

Single-dose bioavailability of two extended-release lithium carbonate products.

The single-dose bioavailabilities of two extended-release lithium carbonate products and an immediate-release product were compared. Nonsmoking healthy volunteers ages 20-31 (n = 12) were randomly assigned to one of three groups and given three treatments, each separated by a one-week period. The treatments, which were given to each group in a different sequence, consisted of three 300-mg immediate-release lithium carbonate tablets (Lithotab), two 450-mg extended-release lithium carbonate tablets (Eskalith CR), and three 300-mg extended-release lithium carbonate tablets (Lithobid). Blood samples were collected just before drug administration and at intervals up to 48 hours afterward. Urine was collected for 96 hours. Plasma and urine lithium concentrations were determined by flame-emission spectrophotometry, and lithium pharmacokinetic values and the cumulative urinary excretion of lithium were computed. Mean maximum plasma lithium concentration (Cmax) differed significantly among all three lithium carbonate products. Eskalith CR produced a 40% lower Cmax and Lithobid a 25% lower Cmax than Lithotab; Lithobid produced a 23% higher Cmax than Eskalith CR. Lithotab had a significantly shorter mean time to maximum plasma lithium concentration than either extended-release product. Mean cumulative urinary excretion of lithium did not differ significantly among the three products. Two extended-release lithium carbonate products were not bioequivalent when given in single doses to healthy volunteers.

Adult↗
PubMed1992

Drug metabolism in the nasal mucosa.

Nasal delivery is a potential alternative for systemic availability of drugs restricted to intravenous administration, such as peptide and protein drugs. Although nasal delivery avoids the hepatic first-pass effect, the enzymatic barrier of the nasal mucosa creates a pseudo-first-pass effect. The xenobiotic metabolic activity in the nasal epithelium has been investigated in several species including humans. The Phase I, cytochrome P-450 enzymes have been studied extensively for their toxicological significance, since these enzymes metabolize inhaled pollutants into reactive metabolites which may induce nasal tumors. The cytochrome P-450 activity in the olfactory region of the nasal epithelium is higher even than in the liver, mainly because of a three- to fourfold higher NADPH-cytochrome P-450 reductase content. Phase II activity has also been found in the nasal epithelium. The delivery of peptides and proteins has been hindered by the peptidase and protease activity in the nasal mucosa. The predominant enzyme appears to be aminopeptidase among other exopeptidases and endopeptidases. The absorption of peptide drugs can be improved by using aminoboronic acid derivatives, amastatin, and other enzyme inhibitors as absorption enhancers. It is possible that some of the surfactants, e.g., bile salts, increase absorption by inhibiting the proteolytic enzymes. Thus, in addition to the permeation barriers, there also exists an enzymatic barrier to nasal drug delivery, which is created by metabolic enzymes in the nasal epithelium.

Absorption↗
PubMed1991

High performance liquid chromatographic determination of theophylline metabolites in human liver microsomes.

A high performance liquid chromatographic (HPLC) technique for the determination of three metabolites of theophylline, 3-methylxanthine (3-MX), 1-methylxanthine (1-MX) and 1,3-dimethyluric acid (1,3-DMU) in human liver microsomes is described. The analytes were extracted from human liver microsomes with methylene chloride/isopropanol and stepwise gradient elution was employed for the resolution of peaks. The limits of quantitation were 15 ng/mL for 3-MX, 20 ng/mL for 1-MX and 20 ng/mL for 1,3-DMU. The calibration range was linear for the three metabolites and the calibration ranges were 15-250 ng/mL for 3-MX, 20-250 ng/mL for 1-MX and 250-4000 ng/mL for 1,3-DMU. The absolute recovery ranged from 63-84% for 3-MX, 65-79% for 1-MX and 77-89% for 1,3-DMU over the calibration curve range. Accuracy for all three metabolites was within +/- 10% and adequate selectivity was demonstrated by the lack of interfering peaks in blank chromatograms. The within-run and interday precision were within 10% RSD for all three metabolites tested at two concentrations. The advantage of this method over previous methods is that the use of quaternary ammonium ion pair reagents in the mobile phase has been obviated. Also, unlike a previous radiometric HPLC method, the need for radiolabelled theophylline has also been eliminated. The method was used to characterize theophylline metabolism in human liver microsomes for immunoinhibition studies and to investigate the interaction of theophylline with selected quinolone antibiotics.

Chromatography, High Pressure Liquid↗
PubMed1989

The effects of storage and shaking on the settling properties of phenytoin suspension.

Phenytoin suspension (PHY-S) is reported to settle, resulting in uneven drug distribution and variable patient dosing. We designed this study to determine the rate of settling and the amount of agitation needed to resuspend the preparation. To determine the rate of settling, we thoroughly shook three bottles of PHY-S and then left them undisturbed. We took samples from the top and bottom of each bottle with a microsyringe at 15 minutes, 1, 6, 12, 24, 48, and 72 hours, and 1, 2, 3, 4, and 5 weeks. We simulated patient administration with daily doses that were measured under good, fair, and poor shaking techniques. We analyzed samples after every tenth dose. After complete resuspension the active ingredient in PHY-S settles at a very slow rate. We found no differences in concentration between the top and bottom until the fifth week in the bottles thoroughly shaken and left undisturbed. Minimal agitation is required to resuspend PHY-S. The well-shaken and poorly shaken bottles in the patient simulation phase exhibited no differences in concentrations whereas the unshaken bottle had differences throughout the study period. Problems thought to be associated with PHY-S may be related to compliance and inaccurate measuring devices.

Drug Storage↗
PubMed1987

Enantiomeric resolution of drug compounds by liquid chromatography.

Novel techniques have recently emerged to separate chiral drug compounds into pure enantiomers. The mechanism, experimental difficulties, and applicability of these methods can very greatly, and the choices involved are not straightforward. The most significant new advances in the field of chiral separations have come from work done with liquid chromatographic systems and chiral stationary-phase columns. This review describes several commonly used approaches to chiral separation, dia-stereomeric derivatization, chiral mobile-phase additives, and three major types of chiral stationary phases. Although no single method can be judged superior for every drug application, it appears that chiral stationary phases have received the most attention recently and they are emphasized here.

Chromatography, High Pressure Liquid↗