Biomedical subjects
Publications and source records attributed to E van der Kleijn.
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A severe case of carbamazepine is described in which the drug and its major metabolite were monitored by means of HPLC. After 2 days of treatment a dramatic rise in plasma concentration of carbamazepine and its metabolite was observed, accompanied by a relapse into deep coma, then followed by a rapid elimination of the drugs and complete recovery within 4 days. The possible mechanisms underlying these phenomena and potential therapeutic measures are discussed.
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The concentration-time curves of carbamazepine (CBZ) and its metabolite (carbamazepine-10,11-epoxide; CBZ-epoxide) were determined in patients undergoing long-term antiepileptic drug treatment with the use of plasma and saliva data. Plasma and saliva samples were assayed concurrently for each patient by liquid chromatography. There was excellent linear correlation between CBZ levels in saliva and plasma (r = 0.991, p less than 0.001) over a large concentration range. The saliva/plasma ratio for CBZ concentration was 0.26 +/- 0.01 (SD). Since CBZ binding to plasma proteins is in the order of 76%, saliva CBZ concentration seems to reflect the unbound fraction of the drug in plasma. CBZ-epoxide has not been detected in saliva. The pharmacokinetic parameters of CBZ-epoxide were determined in 6 patients. The pharmacokinetic parameters of CBZ obtained from saliva concentrations were in excellent agreement with those obtained from plasma concentrations. Thus, CBZ determination in saliva is convenient for controlling blood levels in patients as well as for studying pharmacokinetics. The half-life, the relative body clearance of CBZ, and the metabolite concentration during steady-state, expressed as percent the parent compound, appear to be significantly different in patients on single and combined drug therapy.
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The interactions of antiepileptic drugs in multiple drug treatment have been discussed. Although some combinations may lead to predictable increase or decrease of clearance of the respective drugs, most combinations will individually lead to a reduced predictability. Monitoring plasma concentrations may lead to adaptations of the choice of the drug and of the dosage regimen. Also physiological conditions control the individual clearance of antiepileptic drugs.
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In 14 patients with acute myeloid leukemia (AML) the plasma concentration of cytosine arabinoside (Ara-C) was determined at the start of the first course of treatment at various intervals after a bolus injection. In 10 patients plasma concentration/time data were fitted to a biexponential equation and pharmacokinetic parameters were estimated from the coefficient and exponents of such equations. The plasma half-life (t1/2) of Ara-C of the first phase varied from 1.2 to 1.9 min (mean 1.6). The t1/2 of the second phase varied from 8.8 to 18.9 min. All patients were treated with Ara-C alone in a dose of 100 mg/m2 for 10 or 14 days. There was poor treatment response in five patients with second-phase t1/2 of Ara-C ranging from 6.6 to 10.7 min whereas there was complete remission in nine patients with t1/2 exceeding 12.7 min. In three patients plasma Ara-C concentrations were measured during constant-rate infusion of different amounts of drug. It appeared that the plateau concentrations were directly proportional to the dose, which indicated that in the therapeutic range no enzyme capacity-limited elimination occurs.
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The pharmacokinetics of the anti-epileptic drug di-n-propylacetate (DepakineR) have been studied in 7 patients, in whom plasma concentrations were determined during and following subchronic treatment. Elimination of the drug appeared to follow a monophasic exponential course; biological half lives were 8 to 15 hours. The data supported the assumption that an open one-compartment model can be used to describe the kinetics of dipropylacetate in man. The drug appeared to have a relatively restricted distribution: calculated relative distribution volumes ranged from 0.15 to 0.40 1/kg. There were large interindividual differences in clearance rate. The therapeutic range was considered to be between 50 and 100 mg/1 plasma. Plasma levels of phenobarbital were markedly raised during treatment with dipropylacetate for an unknown reason. Determination of the plasma concentrations of drugs at accurately fixed times appears to be a reliable method for pharmacotherapeutic monitoring of epileptic patients.
A high performance liquid chromatography method for the determination of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole is described. The renal excretion rate and cumulative renal excretion of sulphamethoxazole is markedly influenced by urinary pH. With constant urinary pH, the renal excretion rate and the renal clearance of sulphamethoxazole is dependent on the urine flow. The renal clearance of the metabolite N4-acetylsulphamethoxazole is not influenced by urinary pH or urine flow. No clear acetylator phenotype could be detected in the group of volunteers studied. The extent of acetylation depends on the amount of sulphamethoxazole available for acetylation, thus indirectly on the urine pH and flow.
The pharmacokinetics of N1-acetylsulphamethoxazole and N4-acetylsulphamethoxazole in man are described. N1-Acetylsulphamethoxazole is deacetylated to sulphamethoxazole and acetylated to N4-acetylsulphamethoxazole. N4-Acetylsulphamethoxazole is excreted almost unchanged in the urine. The renal excretion rate is independent of the urine flow and urinary pH. N4-Acetylsulphonamides are less lipid soluble and more acidic than their corresponding parent sulphonamides.