Samira I. Islam

Possible interaction between cyclosporine and glibenclamide in posttransplant diabetic patients

The possible occurrence of a kinetic interaction between cyclosporine A and glibenclamide was assessed by reviewing data of six posttransplant diabetic patients who received the two drugs concurrently. Coadministration of the two drugs resulted in a 57% increase in the steady-state plasma cyclosporine levels despite normal hepatic and renal functions in the patients. This elevation in cyclosporine level is possibly due to an interaction between the two drugs resulting from an inhibition of CYP3A4-mediated metabolism of cyclosporine by glibenclamide. This observation calls for a closer monitoring of cyclosporine plasma levels during concomitant administration of these two drugs in this group of patients.

Simultaneous measurement of phenobarbital, carbamazepine, phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin in serum by high-performance liquid chromatography.

A rapid, highly sensitive high-performance liquid chromatographic method has been developed for the determination of phenobarbital, carbamazepine, phenytoin and its main metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin, in 50 µl of serum. Serum protein was precipitated with an acetonitrile solution containing 5-(4-methylphenyl)-5-phenylhydantoin as the internal standard. The drugs were eluted from a 5 µm, C-18 reversed-phase column at 40 °C with a mobile phase consisting of an acetonitrile-methanol-phosphate buffer of pH 4.8 (22 + 28 + 50%V/V), at a flow-rate of 1 ml min–1 with UV detection at 214 nm. Each analysis required no longer than 12 min. Quantitation was achieved by the measurement of the peak-height ratio and the relative and absolute recoveries varied from 94 to 109%. Within-day coefficients of variation ranged from 1.2 to 3.22% and between-day coefficients of variation from 2.0 to 3.4% in subtherapeutic, therapeutic and toxic concentrations.

Comparison of fluorescence polarization immunoassay and high performance liquid chromatography for the quantitative determination of phenytoin, phenobarbitone and carbamazepine in serum

The Abbott TDx fluorescence polarization immunoassay (FPIA) system has been evaluated and compared with well‐established high performance liquid chromatography (HPLC) for the determination of three anticonvulsant drugs: phenytoin, phenobarbitone and carbamazepine. These assays were evaluated for precision, calibration curve stability, specificity and accuracy. Within‐run precision studies using control samples (n = 15) in the subtherapeutic, therapeutic, and toxic concentrations, resulted in coefficients of variation in the range of 1.79–3.99% (FPIA) and 1.16–2.52% (HPLC), respectively. Between‐run precision ranged from 2.32–6.34% for FPIA and from 2.04–3.38% for HPLC. Comparison of 122 patient samples assayed with both methods indicated an extremely good analytical correlation (r = 0.96) for all three comparisons. The FPIA method offers significant advantages in calibration curve stability while maintaining accuracy and precision comparable with those of established HPLC procedures.

Polymorphic acetylation of sulphamethazine in rural bedouin and urban-dwellers in Saudi Arabia

1. The polymorphic acetylation of sulphamethazine (sulphadimidine, sulphamezathine) has been investigated in a population of 109 Saudi male arabs of rural bedouin origin and in 126 Saudi female arabs from urban cosmopolitan areas of Jeddah. 2. Rural males excreted 5-79% of the administered dose (1 X 5 g/m2 body surface area) in the 0-12 h urine and the urban females excreted 5-97%. 3. The frequency distribution of the ratio acetyl sulphamethazine/sulphamethazine was bimodal in rural, urban and the combined populations with a clear antimode at 70% acetylation of the recovered dose. 4. The incidence of slow acetylators was 67 X 9, 59 X 5 and 63 X 4% in the rural, urban and combined populations. The incidence of the As allele in Saudi arabs was thus 0 X 80+/-0 X 03 S.E.M., which is similar to that found in the neighbouring countries, of Egypt and Sudan. Since no significant difference in As frequency was apparent between the rural (pure) and urban (cosmopolitan) arabs, it is concluded that immigrants to Saudi Arabia from other muslim countries have not affected the gene frequencies with respect to acetylation. 5. Methodology of assessing acetylation phenotype is discussed. It would appear that urine analysis alone gives satisfactory discrimination between phenotypes.

Inhibition of lipid peroxide decomposition by compounds which bind with cytochrome p-450

The kinetics of lipid peroxide decomposition catalysed by microsomal enzymes and inhibited by SKF-525 A, hexobarbital, phenobarbital and aniline were investigated. The results indicate that the in vitro interaction of hexobarbital and SKF-525 A (type I binding compounds) with microsomal cytochrome p-450 inhibits the peroxidase activity while the in vitro interaction of aniline (type II binding compound) only slightly affect the peroxidase activity. It is suggested that LAHPO and type I binding compounds are competing for the hydrophobic binding site on cytochrome p-450, while type II binding compounds such as aniline negate electron transfer non-competitively by combining with the heme.

Comparison of the fluorescence polarization immunoassay and the microbiological assay methods for the determination of gentamicin concentration in human serum.

The performance of the fluorescence polarization immunoassay (FPIA) was compared with that of a microbiological assay for the measurement of serum gentamicin concentrations. Within-run precision from duplicate assays of two concentrations (4 and 8 micrograms/ml) using FPIA and the microbiological assay yielded coefficients of variation (r) of 2.62%, 1.76% (n = 12) and 8.06%, 6.87% (n = 12), respectively. Day-to-day precision was estimated by repetitive analysis of 4 and 8 micrograms/ml control samples over a 3-week period. Coefficients of variation (r) were 2.57%, 3.09% (n = 8) and 10.71%, 14.20% (n = 8) for FPIA and the microbiological assay, respectively. Linear regression analysis performed on data from parallel determinations on 143 patient samples by the two methods showed correlations in the order of 0.74. The FPIA offers a rapid, efficient, and accurate system for therapeutic monitoring of gentamicin serum levels.

CORRELATION BETWEEN PREDICTED AND MEASURED DIGOXIN SERUM CONCENTRATIONS

Measurement of digoxin serum concentration can be useful as a direct guide to the dose appropriate to individual patients. Therefore, we have attempted to predict digoxin serum concentration in 62 patients with a wide range of body weight, age and renal function, using creatinine clearance and individual digoxin dose. Creatinine clearance in each patient was determined by the Cockroft and Gault method (1). Digoxin clearance was determined by Scheiners method (2). Once digoxin clearance was determined, the predicted steady‐state serum concentration was calculated using general pharmacokinetic principles. Each patient was on digoxin therapy for at least 1 month. Digoxin serum concentration was measured by the newly developed fluorescence polarization immunoassay (FPIA). A linear regression analysis was performed on the data from the predicted and measured serum level which yielded a slope of 0·9463 intercept of 0·0950 and a correlation coefficient (r) of 0·9600. The method was found to be very useful to predict digoxin serum levels in overdosed and underdosed patients.

Acetylation phenotyping of isoniazid using a simple and accurate high-performance liquid chromatography.

A simple, specific, accurate and reproducible method for the analysis of isoniazid and its major metabolite, N‐acetylisoniazid in urine using high‐performance liquid chromatography (HPLC) is described. The assay is performed after extraction of isoniazid, N‐acetylisoniazid and 5‐(4‐methylphenyl)‐5‐phenylhydantoin (internal standard) from urine using a mixture of chloroform: isopropanol (70:30, v/v) and eluted from a 5 urn C‐18 reversed phase column at ambient temperature with a mobile phase consisting of 10 mM sodium acetate: methanol: acetonitrile (40:40:20, v/v) containing 10 mM dioctylsulphosuccinate sodium and adjusted to pH 2·9 with sulphuric acid (< 1 ml), at a flow rate of 1 ml/min with u.v. detection at 266 nm. Quantification was achieved by the measurement of the peak height ratio, and the absolute recoveries ranged from 94 to 99%. Within‐day coefficients of variation ranged from 2·81 to 4·54% for isoniazid and from 2·37 to 3·75% for N‐acetylisoniazid. Between‐day CVs varied from 3·27 to 5·62% and from 2·5 to 4·91% for isoniazid and N‐acetylisoniazid, respectively. Preliminary stability tests using a urine sample from a subject showed an increase in mean isoniazid concentration of about 25% after 1 month storage at ‐ 20°C. The method was used for acetylation phenotyping of five individuals.