Renal excretion and pharmacokinetics of methotrexate and 7-hydroxy-methotrexate following a 24-h high dose infusion of methotrexate in children.

In children with lymphoid malignancies 18 courses of methotrexate (18-200 mg/kg) administered as a 24-h infusion were monitored. Plasma concentrations and renal excretion rates of methotrexate (MTX) and 7-hydroxymethotrexate (7-OHMTX) were determined. A low correlation was found between the administered dose of MTX and the body exposure to MTX or 7-OHMTX. Although 84% of the MTX eventually recovered from the urine was excreted during the 24 h of the infusion, the renal clearance of MTX was markedly lower during the time of the infusion than after it. There were courses with a low and others with a high renal clearance of MTX during the infusion, despite the same urine flow. A low MTX renal clearance was correlated with a high body exposure to MTX. As the same variations were also seen in the same patient during successive courses, pharmacokinetical characterization of patients appears questionable. The renal clearance of 7-OHMTX was significantly lower than the renal clearance of MTX, and the body exposure to 7-OHMTX ranged from 2-40% of the MTX body exposure. Treatment courses with a low or a high body exposure to 7-OHMTX were not associated with different urinary recoveries of the metabolite. Differences in MTX hydroxylation could not be substantiated. Because the concentration of 7-OHMTX is high soon after the end of an infusion, a specific method of MTX determination should be chosen for controlling treatment.

Comparison of linear and tapered intravenous infusion of methotrexate in oncochemotherapy. A theoretical approach.

In oncochemotherapy with methotrexate (MTX) a peripheral concentration greater than 0.45 mg/l and a plasma concentration less than 45 mg/l must be maintained for 20 h. The time periods required to reach and maintain steady-state concentrations after tapered and linear intravenous infusion were compared. Pharmacokinetic analyses according to a two-compartment model were used to calculate dosage regimens and concentration profiles by means of the Bayesian General Modelling Program (BM) and NONLIN. When the dosage regimen is based on a steady-state concentration in the peripheral compartment (which is the target compartment for MTX) tapered infusion reaches this concentration 40% faster and maintains it 12.5% longer, but no difference is found if the dosage regimen is based on a steady-state concentration in the central compartment. In theory the two-step 24-hour tapered infusion can be replaced by a bolus injection plus linear infusion in the ratio 1:2 of the total dose. These dosage regimens are to be preferred over linear infusion.

Some pitfalls in selecting descriptive pharmacokinetic models.

Some pitfalls in selecting pharmacokinetic models are enumerated. To calculate the pharmacokinetic parameters of a drug that exhibits a biphasic convex plasma concentration-time curve, a two-compartment model does not automatically have to be applied. When only the parent drug in plasma is considered, a two-compartment model seems to be most appropriate. However, when the kinetic behavior of the metabolite has to be taken into account, and when a metabolic equilibrium underlies the metabolic elimination, the two-compartment model may not be appropriate. Also, when calculating the kinetic parameters of a drug with a concave biphasic plasma concentration-time curve, a capacity-limited metabolic conversion is not the automatic explanation for this observation. Limitations in renal excretion and bioavailability may be the reasons for this behavior. Convex and concave biphasic plasma concentration-time curves are illustrated, using sulfonamides as test compounds.

Effects of methoxy groups in the NI-substituent of sulfonamides on the pathways of elimination in man. The acetylation-deacetylation equilibrium and mechanisms of renal excretion of sulfisomidine, sulfamethomidine and sulfadimethoxine.

Sulfisomidine, sulfamethomidine, sulfadimethoxine and their corresponding N4-acetyl derivatives were administered to man. The percentages of acetylation and deacetylation and those of protein binding, the half-lives of elimination and the apparent and true renal clearance values were measured. No acetylation phenotype could be demonstrated in these compounds. Methoxy substitution in the NI-pyrimidine group of sulfisomidine affects predominantly the renal clearance value and mechanism of the parent compound but has no influence on the renal clearance of the N4-acetyl derivatives. The renal clearance value of sulfisomidine is 232 +/- 33 ml/min, of sulfamethomidine 21.60 +/- 16.4 ml/min and of sulfadimethoxine 10.87 +/- 10.44 ml/min. The renal clearance values of the corresponding N4-acetylsulfonamide derivatives are 314 +/- 91 ml/min, 342 +/- 63 ml/min and 202 +/- 65 ml/min respectively. Tubular reabsorption, caused by methoxy substitution in the NI-pyrimidine ring, lowers the rate of elimination and increases the half-life. The half-life of sulfisomidine is 8.5 +/- 0.5 h, of sulfamethomidine 27.8 +/- 5.3 h and of sufadimethoxine 34.6 +/- 10.4 h.

Rapid quantitative determination of seven anthracyclines and their hydroxy metabolites in body fluids.

A reversed-phase high-performance liquid chromatographic method is described for the determination of seven anthracycline analogues and their hydroxy metabolites. The method is suitable for analysis of 30 plasma samples a day. The detection limit is 0.5 ng/ml for all compounds. Examples of the pharmacokinetics of adriamycin and carminomycin in man are shown.

Pharmacokinetics of anthracyclines in dogs: evidence for structure-related body distribution and reduction to their hydroxy metabolites.

The pharmacokinetic disposition of the anthracyclines, adriamycin (doxorubicin), daunorubicin, 4'-epi-adriamycin, carminomycin, and 4-demethoxy-daunorubicin, and the formation of their reduced C13 hydroxy metabolites were studied in dogs. The presence of a C14hydroxy group (adriamycin and 4'epi-adriamycin) drastically reduces the appearance of the C13 hydroxy metabolites in plasma. Substitution of the C4-H with C4-OH and C4-OCH3, in this rank order, decreases the area under the plasma concentration-time curves of the parent compounds and their C13 hydroxy metabolites.

Determination of sparsomycin in plasma and urine of the dog by means of reversed-phase high-performance liquid chromatography and first pharmacokinetic results.

Sparsomycin--an antibiotic with marked cytostatic activity--was the subject of a clinical Phase I study in 1964. The structure of sparsomycin was elucidated in 1970 and its first total synthesis was reported in 1981. Here we describe a sensitive high-performance liquid chromatographic method of determination. The detection limit was found to be 10 ng/ml of plasma and 20 ng/ml of urine. With this procedure sparsomycin and isosparsomycin can readily be separated. In addition, we performed a first pharmacokinetic study in the dog and found a half-life time t1/2 beta of 1.1 h. Only 25% of the administered dose could be recovered in the urine as sparsomycin. We consider that by now many prerequisites for further preclinical studies have been achieved, and the results of these studies will determine whether sparsomycin deserves reintroduction into clinical use.