Eppo van der Kleijn

KINETICS OF CARBAMAZEPINE AND CARBAMAZEPINE-EPOXIDE, DETERMINED BY USE OF PLASMA AND SALIVA

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 < 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.

Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia

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 (t½) of Ara‐C of the first phase varied from 1.2 to 1.9 min (mean 1.6). The t½ 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 t½ of Ara‐C ranging from 6.6 to 10.7 min whereas there was complete remission in nine patients with t½ 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.

Determination of 5-methyltetrahydrofolic acid in plasma and spinal fluid by high-performance liquid chromatography, using on-column concentration and electrochemical detection

Chromatographic conditions for the determination of 5-methyltetrahydrofolic acid in plasma and spinal fluid are described, involving simple pretreatment of the sample. Electrochemical detection was used. The linear range of the method is more than 10(3). Recovery from plasma and spinal fluid is 100%, and the detection limit of the method is 2.10(-9) M, sufficient for the detection of endogenous plasma and spinal fluid levels. The detection conditions are discussed. Endogenous concentrations of the compound in plasma and spinal fluid were determined and correlated with a folate bioassay. Plasma concentrations have been shown after the administration of leucovorin which is used in anticancer therapy.

Gas chromatographic determination and pharmacokinetics of 4-hydroxybutyrate in dog and mouse

A rapid and reproducible method was developed to extract 4-hydroxybutyrate from plasma as 4-butyrolactone for subsequent gas chromatographic (GLC) assay. The drug, an intravenous anesthetic and oral hypnotic in man, was infused into four dogs and the plasma concentration was determined by14C-isotope dilution and GLC. Pharmacokinetic parameters for distribution and elimination were calculated. A capacity-limited process appears to be involved in the elimination of 4-hydroxybutyrate in the dog. Macroautoradiography revealed the distribution pattern in normal and pregnant adult mice.

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.

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.

Gas chromatographic determination of ethosuximide and phensuximide in plasma and urine of man

Ethosuximide and phensuximide in plasma and urine can be assayed to a concentration of 2–5 μg ml−1 by a rapid and specific gas chromatographic assay. The method can be used to monitor plasma concentrations in patients with petit mal treated with these drugs alone or in combination with other antiepileptic drugs. The steady‐state plasma concentrations of ethosuximide in children given 10–45 mg kg−1 day−1 varied between 10 and 150 μg ml−1 indicating marked interindividual differences in pharmacokinetics.

Significance of Apparent Half-Lives of a Metabolite with a Higher Elimination Rate Than its Parent Drug

where Ctm is plasma concentration of the metabolite of a drug at time t, following the administration of the parent drug at time t = 0; A and B are constants; k., is rate constant of metabolism (acetylation or glucuronidation); and k., is rate constant of elimination. (This may consist of the rate constant of metabolism [km] and the renal excretion [k r ] . ) If the elimination rate of the metabolite is faster than the rate of formation, then the term of the elimination diminishes faster than the term of the formation. Consequently, the rate of formation becomes the rate-limiting factor. This statement is valid in all situations in which one particular metabolic reaction, parent drug-metabolite, is considered, independently of many parallel pathways of elimination. Thus, when the intrinsic elimination of the metabolite is faster than that of the parent compound, the plasma concentration time curves of both compounds must run parallel. 1 This behavior is seen with sulfonamide drugs and their Nr-acetylsulfonamide metabolites as well as with many other compounds undergoing glucuronidation. To determine the intrinsic rate of elimination of the

Change in Transfer Rate of Methotrexate from Spinal Fluid to Plasma during Intrathecal Therapy in Children and Adults

AbstractMethotrexate’ plasma concentrations were measured repeatedly over 48 hours after each of 5 subsequent intrathecal injections in 14 children and 8 adult patients with acute lymphoblastic leukaemia. Two patterns of concentration profiles were distinguished: a)The plasma concentration reached a rather low maximum, followed by a relatively slow decline (‘slow type’)b)The plasma concentration increased rapidly to a relatively high value after which it declined rather steeply (‘fast type’). The incidence of the ‘fast type’ increased progressively with the number of intrathecal injections.When the plasma concentration-time curves were described by a pharmacokinetic 2-compartment open model with first-order absorption, it was calculated that the transfer of methotrexate front the spinal fluid into the plasma is much slower for the ‘slow type’ compared with the ‘fast type’.Assuming concentration-dependent cytostatic activity, the therapeutic efficacy in the central nervous system is likely to be less for the ‘fast type’ than for the ‘slow type’. Systemic toxicity resulting from the ‘slow type’ is expected to be higher than from the ‘fast type’.

Pharmacokinetics and Anticonvulsant Activity of Three Monoesteric Prodrugs of Valproic Acid

The pharmacokinetics of valproic acid (VPA) were compared in dogs with those of the prodrugs ethyl valproate (E-VPA), trichloroethyl valproate (T-VPA), and valproyl valproate (V-VPA). Valproic acid, E-VPA, T-VPA, and V-VPA were administered intravenously and orally to six dogs at equimolar doses. The three VPA prodrugs were rapidly converted to VPA. The biotransformation was complete in the case of E-VPA and T-VPA but was only partial in the case of V-VPA. Because of the rapid conversion to the parent drug, after administration of the prodrugs, VPA plasma levels did not yield a sustained-release profile. Further, the anticonvulsant activity of prodrugs was compared in mice to that of VPA and valpromide (VPD). The anticonvulsant activity of E-VPA, T-VPA, and V-VPA was less than that of VPA.