K. M. Matar

Liquid chromatographic determination of six antiepileptic drugs and two metabolites in microsamples of human plasma.

A simple, rapid, sensitive, and reproducible high-performance liquid chromatographic (HPLC) method for simultaneous determination of the antiepileptic drugs (ethosuximide, primidone, lamotrigine, phenobarbital, phenytoin, and carbamazepine) and two metabolites (carbamazepine-diol and carbamazepine-epoxide) in human plasma is described. The procedure involves extraction of the drugs from human plasma (100 microL) with ether using 9-hydroxymethyl-10-carbamyl acridan as an internal standard. The extract was evaporated and reconstituted with mobile phase and then injected onto the chromatograph. The drugs and the internal standard were eluted from a Supelcosil LC-18 stainless steel column at ambient temperature with a mobile phase consisting of a 0.01M phosphate buffer/methanol/acetonitrile (65/18/17, v/v/v) adjusted to a pH of 7.5 with phosphoric acid and a flow rate of 1 mL/min. The effluent was monitored at 220 nm. Quantitation was achieved by using peak area ratio of each drug to the internal standard. The intraassay and interassay coefficients of variation (CV) ranged from 2.43% to 6.25% and from 3.02% to 5.85%, respectively. The absolute (extraction) and relative (analytical) recoveries for the drugs ranged from 70.7% to 104.4% and from 88.3% to 106.1%, respectively. Stability tests showed that the drugs were stable in plasma for at least 4 weeks when stored at -20 degrees C. The method was applied clinically for monitoring the AEDs in epileptic patients.

A rapid liquid chromatographic method for the determination of lamotrigine in plasma

A rapid sensitive and simple high-performance liquid chromatographic (HPLC) method for the determination of lamotrigine in plasma is described. The drug was extracted from 100 microliters of plasma with chloroform:isopropanol (95:5% v/v) in the presence of 100 microliters of phosphate buffer (10 mM). The extract was evaporated and the residue was reconstituted with mobile phase and injected onto the HPLC system. The drug and the internal standard (chloramphenicol) were eluted from a Symmetry C18 stainless steel column at ambient temperature with a mobile phase consisting of 0.01 M potassium-acetonitrile-methanol (70.20:10% v/v/v), adjusted to pH 6.7, at a flow rate of 1.3 ml min-1 and the detector was monitored at 214 nm. Quantitation was achieved by measurement of the peak-area ratio of the drug to the internal standard and the lower limit of detection for lamotrigine in plasma was 20 ng ml-1. The intraday precision ranged from 3.34 to 6.12% coefficient of variation (CV) and the interday precision ranged from 2.15 to 8.34% CV. The absolute and relative recoveries of lamotrigine ranged from 86.93 to 90.71% and from 95.18 to 107.13%, respectively. The method was applied in studying the pharmacokinetics of lamotrigine administered orally to rabbits. This reliable micro-method would have application in pharmacokinetic studies of lamotrigine where only small sample sizes are available, e.g. paediatric patients.

Effects of Pregnancy on the Pharmacokinetics of Lamotrigine in Dogs

Summary: Purpose: This study was designed to evaluate the effects of pregnancy on the kinetics of lamotrigine (LTG).

A Simple, Specific, and Rapid High Performance Liquid Chromatographic Assay for Glibenclamide in Plasma

Abstract A simple, rapid, sensitive and relatively specific reverse phase HPLC assay procedure for glibenclamide in rat and human plasma is described. The method employs considerably smaller sample volume (0.2 ml) and a single step extraction with dichloromethane. A relatively high degree of sensitivity (detection limit of the assay was 20 ngml−1) was obtained by using fluorescence detection at excitation and emission wavelengths of 308 and 360 nm, respectively. The mean percentage recovery of the drug in the concentration range of 30–120 ng was 100.6% while the between-day coefficient of variation for the same concentration range was 7.29%. The assay procedure offers a much better degree of resolution for the glibenclamide peak than was previously reported. This was achieved through the use of a chromatographic column with a finer packing material (Novapak C18, 4 μm) and by selecting the ideal composition, pH and elution rate of the mobile phase—methanol: 0.05 M potassium dihydrogen phosphate (61:39 v/v,...

Effect of valproic acid on the pharmacokinetic profile of oxcarbazepine in the rat

The pharmacokinetics of oxcarbazepine (30 mg kg-1, po), administered for 1 week, was studied in rats pre-treated for 2 weeks with valproic acid (100 mg kg-1, po). Oxcarbazepine (OXC) plasma levels were measured over a period of 24 h from dosing, using a sensitive HPLC method. No significant changes were observed in the mean values of OXC pharmacokinetic parameters (Cmax, Tmax, t1/2 and AUC0-infinity) between the control and the pre-treated groups. The findings of this study suggest that OXC metabolism in the rat is apparently not affected by valproic acid, and the lack of effect may be attributed to the different pathways of biotransformation of the two drugs.

The interaction potential of vigabatrin with phenytoin and carbamazepine

Abstract The effect of vigabatrin on the pharmacokinetic profiles of orally coadministered doses of phenytoin (PT) and carbamazepine (CBZ) was examined in the rat. Plasma PT and CBZ levels were serially monitored over a 24 h period using an HPLC technique. Coadministration of vigabatrin markedly delayed drug absorption (i.e., longer T max ) and significantly reduced the plasma levels of PT and CBZ as assessed by the depression in the respective AUCs. These corresponded to a reduction of 21 and 17%, respectively. The effect on plasma drug concentration was not paralleled by any significant change in the elimination half-lives (t 1 2 ) of the drugs. The similarity in the pattern and magnitude of interaction observed with both drugs suggests a common underlying mechanism. In the absence of hepatic factors, and with vigabatrins negligible influence on plasma protein binding, gastrokinetic property for vigabatrin is proposed as a likely mechanism to account for the interactions, but clearly further studies are needed to firmly establish this drug action.

Effect of vigabatrin and gabapentin on phynytoin pharmacokinetics in the dog

SummaryThe study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP).A group of five beagle dogs were given a daily dose of PT (12 mg/kg, i.v.) for a period of 1 week. On day 8, plasma samples were serially collected over 24 hr. after administration of the PT dose. PT administration was continued with oral supplementary dose of VGB (60 mg/kg) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mg/kg, IV) — GBP (300 mg caps., PO) study on a separate group (n=5) of dogs.Orally administered GBP did not significantly alter the pharmacokinetic parameters of parentral PT. VGB, however markedly changed the drug’s kinetics as evidenced by a 31% (P=0.015) reduction in total body clearance (CL) and increase of over 45% in half-life (t1/2), (P=0.013) and area under the plasma PT concentration-time curve (AUC), (P=0.044).GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in marked reduction in systemic clearance of the latter in the dog.

Effect of famotidine on theophylline pharmacokinetics in the rat

The effect of famotidine (4 mg/kg p.o.) on the pharmacokinetic profile of coadministered theophylline was studied in the rat. Plasma theophylline concentration was measured serially for 12 h by HPLC. Peak plasma levels (Cpmax) and the time at which these were attained (Tmax) were not significantly altered during coadministration. There were, however, reductions in both the elimination half-life (t12) and the area under the curve (AUC) but only the changes in the latter parameter reached the level of significance. These data suggest that the kinetic interaction between famotidine and theophylline is very limited and that it may feature hepatic enzyme induction as opposed to the inhibitory effect documented for cimetidine.

High Performance Liquid Chromatographic Determination of (-)-N-Formylnorephedrine in Plasma

Abstract An HPLC procedure for the detection and quantitative estimation of (-)-N-formylnorephedrine in rabbit plasma had been developed. The procedure involved the extraction of (-)-N-formylnorephedrine from plasma spiked with the internal standard (phenacetin), using ethyl acetate. The ethyl acetate extract is evaporated under nitrogen and the residue is reconstituted in water and injected onto the column. A u-Bondapak-C18 column 30 cm × 3.9 mm ID was used. The mobile phase is 20% acetonitrile in water; at a flow rate of 1.5 ml/min and uv detection at 256 nm. A linear relationship between concentration and peak height ratio (I/internal standard) was obtained (r = 1.00). The reported procedure allows the measurement of (-)-formylnorephedrine in concentrations as low as 150 ng/ml of plasma with total procedure time of about 10 min. The applicability of the procedure to pharmacokinetic studies is illustrated and metabolites are shown not to interfere with the assay procedure.

Assessment of pharmacokinetic interaction between theophylline and loperamide in the rat

SummaryThe effect of loparamide (1 mgkg−1, p.o.) on the pharmacokinetics of theophylline was studied in the rat. Theophylline (as aminophylline-25 mgkg−1, p.o.) was administered either alone, in combination with, or 1 hr after loperamide. Plasma levels of theophylline were serially measured over a period of 12 hr using HPLC. The disposition kinetics of theophylline was markedly altered by loperamide. This was evident from the significant differences obtained between the control and drug combination groups in most of the parameters studied (Cpmax, tmax, Ka, tl/2 and AUC). Allowing for the limitations of single dose studies, the data presented here suggest that pharma — cokinetic interaction between theophylline and loperamide is possible during their comcomitant use.