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J H Schellens

Publications and source records attributed to J H Schellens.

132 records · Page 8Linked to original sources
PubMed1988

Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a 'cocktail' approach.

1. Three model substrates for the characterization of drug oxidation activity, antipyrine (AP), hexobarbitone (HB) and theophylline (TH), were administered to 26 healthy volunteers on two different occasions: in the first experiment a combination of AP (250 mg) and HB (250 mg) was given and in the second experiment TH (150 mg) was added to the former combination. 2. Plasma concentrations of AP, HB and TH and urinary excretion of TH and the three main metabolites of AP (3-hydroxymethylantipyrine: HMA, norantipyrine: NORA and 4-hydroxyantipyrine: OHA) were determined and the intrinsic clearance (CLint) of the three substrates and the clearance to the formation of AP metabolites were calculated. 3. The correlation coefficients between CLHB and CL-greater than metabolites of AP were highest for CL-greater than HMA and CL-greater than NORA (greater than 0.80) and lowest for CL-greater than OHA (0.63). High correlation coefficients also were found between CLTH and CL-greater than OHA (0.89) and CL-greater than HMA (0.80). 4. Ideal relationships, defined by a slope of the orthogonal regression line equal to unity, did exist between CLHB and CL-greater than HMA as well as CL-greater than NORA and between CLTH and CLAP as well as CL-greater than OHA. 5. Based on the results of correlation and regression analysis it can be concluded that isozymes of the cytochrome P-450 system responsible for the oxidation of HB and formation of HMA and NORA are very closely related and also that isozymes responsible for the oxidation of TH and formation of OHA show a very close relation. 6. With this strategy of simultaneous administration of substrates ('cocktail' approach) it seems possible to characterize and correlate activities of different P-450 isozymes and to investigate their in vivo substrate selectivity without the disturbing influence of intra-individual variation in drug oxidation.

Adult↗
PubMed1987

Variability in drug metabolism: importance of genetic constitution.

In man wide variability exists in the rate of metabolism of drugs and among factors which contribute to this phenomenon genetic constitution is of major importance. The metabolism of a number of drugs is subject to polymorphism and the frequency distribution of particular pharmacokinetic parameters shows bimodality, with poor (PM) and extensive metabolizers (EM). Acetylation of a number of drugs is known to be polymorphic and the incidence of poor metabolizers varies markedly among different populations. Debrisoquine and sparteine are frequently applied model substrates for the characterization of a polymorphism in oxidative metabolism. Polymorphic drug oxidation may have important clinical implications, because when standard dosage regimens are applied plasma concentrations will reach far above the maximum acceptable in poor metabolizers and consequently side effects may arise. Regarding the multiplicity of the drug oxidizing enzyme system (cytochrome P-450) it could be of interest to combine model substrates in a cocktail to be able to characterize human subjects simultaneously for a number of independent polymorphisms.

Acetylation↗
PubMedDate not supplied

Cyclosporine-induced anaphylaxis.

OBJECTIVE: To describe a case of an anaphylactic reaction after first ingestion of oral cyclosporine capsules (Neoral). CASE SUMMARY: A 73-year-old white woman was admitted for the treatment of metastatic breast carcinoma with an experimental oral paclitaxel solution in combination with cyclosporine capsules. After ingestion of the cyclosporine capsules, the patient collapsed within one hour. She initially experienced severe hypotension and bradycardia. After a few minutes, she developed severe tachycardia, dyspnea, and decreased consciousness. Administration of epinephrine, dexamethasone, clemastine, oxygen, and gelofusine (succinylated gelatin 4% in NaCl 0.9%) infusion resulted in complete recovery after several hours. The planned oral paclitaxel administration was canceled. Intravenous paclitaxel was given the next day, preceded by standard premedication with dexamethasone, clemastine, and cimetidine, without complications. DISCUSSION: To our knowledge, this is the first report in the literature of an anaphylactic reaction after oral ingestion of cyclosporine capsules. Earlier reports of anaphylaxis concerned intravenous cyclosporine or oral solutions of cyclosporine (both Sandimmune). These anaphylactic reactions were considered to be due to the pharmaceutical vehicle Cremophor EL or related substances, which are well-known causes of anaphylaxis. The capsules used in this case contain the Cremophor EL-related polyoxyl 40 hydrogenated castor oil as a base; our patient's anaphylactic shock may have been due to this substance. CONCLUSIONS: In addition to earlier reports about anaphylactic reactions after administration of an intravenous or oral solution of cyclosporine, this case shows that anaphylactic shock can occur after ingestion of cyclosporine capsules.

Administration, Oral↗