E. van der Kleijn

Pharmacokinetics of di-n-propylacetate in epileptic patients.

SummaryThe 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.

Plasma and urinary excretion kinetics of oral baclofen in healthy subjects

SummaryBaclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured.After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14) %. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data.The renal excretion rate constant had the high mean value of 0.35 (0.24) h−1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH.Although active tubular secretion may contribute to its renal clearance, as shown by the effect of coadministration of probenecid, glomerular filtration appears to be the dominant transport mechanism.

Determination of trimethoprim and sulfamethoxazole (co-trimoxazole) in body fluids of man by means of high-performance liquid chromatography

A high-performance liquid chromatographic method for the determination of trimethoprim, sulfamethoxazole and its metabolite and a series of structurally related sulfonamides is described. The half-life time of elimination of sulfamethoxazole and its metabolite N4-acetylsulfamethoxazole is 9 h for both compounds. The renal excretion rate of sulfamethoxazole depends strongly on the urinary pH. The renal excretion rate of the metabolite N4-acetylsulfamethoxazole is not dependent on the urinary pH.

Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

SummaryA 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.

Determination of the Acetylator Phenotype and Pharmacokinetics of Some Sulphonamides in Man

The pharmacokinetics of sulphamethizole, sulphamethoxazole, sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow.N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processed by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processed by I acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min−1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.

Statistical Analysis of Pharmacokinetic Parameters in Epileptic Patients Chronically Treated with Anti­ Epileptic Drugs

For the management of epileptic seizures, a single anti-epileptic drug or a combination of drugs has been used with variable success. Although blood level determinations are not yet available for the majority of the physicians who prescribe these medications, these data are meant to support the optimum control of the number of seizures (Buchthal and Svensmark, 1971; Rose et al., 1971; Koch-Weser, 1972; Woodbury et al., 1972, Gardner-Medwin, 1973).

Pharmacokinetics of N1-Acetyl- and N4-Acetylsulphamethoxazole in Man

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.

Effects of zopiclone and temazepam on sleep, behaviour and mood during the day

SummaryOver a 3 week period the hypnotic effect of zopiclone 7.5 mg, temazepam 20 mg and placebo was investigated in a double-blind, cross-over study in 60 out-patients.The hypnotic effect, subdivided in the parameters sleep quality, latency of sleep onset and status after awaking, was scored daily by the patient after arising. The results showed that zopiclone 7.5 mg and temazepam 20 mg were almost equally effective. In sleep quality and latency of sleep onset, there appeared to be a non-significant trend favouring zopiclone. Both hypnotics differ significantly from placebo.Mood and behaviour during the day, as well as somatic symptoms and side-effects, were also scored daily and showed no significant differences between the treatments.The third week, which was a placebo week for all patients, showed a gradual improvement in sleep quality. It supports the case for not prescribing hypnotics for more than 2 weeks.

Determination of tranquillizers by GLC in biological fluids

Abstract Procedures for the gaschromatographic assay of ataractic drugs or tranquillizers as well as their pharmacologically active metabolites have been given. The assays are simple and rapid. They allow qualitative identification and a quantitative persuit of the patients treatments. In cases of overdosing the identity is necessary for the choise of the treatment, whereas the progress can be based on the concentrationtime course of drug and possibly of metabolites. A discussion on the relevance of the measured values has been given.