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G J Sanderink

Publications and source records attributed to G J Sanderink.

13 recordsLinked to original sources
PubMed1997

Involvement of human CYP1A isoenzymes in the metabolism and drug interactions of riluzole in vitro.

Cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes involved in riluzole oxidation and glucuronidation were characterized in (1) kinetic studies with human hepatic microsomes and isoenzyme-selective probes and (2) metabolic studies with genetically expressed human CYP isoenzymes from transfected B-lymphoblastoid and yeast cells. In vitro incubation of [14C]riluzole (15 microM) with human hepatic microsomes and NADPH or UDPGA cofactors resulted in formation of N-hydroxyriluzole (K(m) = 30 microM) or an unidentified glucuroconjugate (K(m) = 118 microM). Human microsomal riluzole N-hydroxylation was most strongly inhibited by the CYP1A2 inhibitor alpha-naphthoflavone (IC50 = 0.42 microM). Human CYP1A2-expressing yeast microsomes generated N-hydroxyriluzole, whereas human CYP1A1-expressing yeast microsomes generated N-hydroxyriluzole, two additional hydroxylated derivatives and an O-dealkylated derivative. CYP1A2 was the only genetically expressed human P450 isoenzyme in B-lymphoblastoid microsomes to metabolize riluzole. Riluzole glucuronidation was inhibited most potently by propofol, a substrate for the human hepatic UGT HP4 (UGT1.8/9) isoenzyme. In vitro, human hepatic microsomal hydroxylation of riluzole (15 microM) was weakly inhibited by amitriptyline, diclofenac, diazepam, nicergoline, clomipramine, imipramine, quinine and enoxacin (IC50 approximately 200-500 microM) and cimetidine (IC50 = 940 microM). Riluzole (1 and 10 microM) produced a weak, concentration-dependent inhibition of CYP1A2 activity and showed competitive inhibition of methoxyresorufin O-demethylase. Thus, riluzole is predominantly metabolized by CYP1A2 in human hepatic microsomes to N-hydroxyriluzole; extrahepatic CYP1A1 can also be responsible for the formation of several other metabolites. Direct glucuronidation is a relatively minor metabolic route. In vivo, riluzole is unlikely to exhibit significant pharmacokinetic drug interaction with coadministered drugs that undergo phase I metabolism.

Biotransformation↗
PubMed1996

Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans.

Docetaxel metabolism mediated by cytochrome P450-dependent monooxygenases was evaluated in human liver microsomes and hepatocytes. In microsomes, the drug was converted into four major metabolites resulting from successive oxidations of the tert-butyl group on the synthetic side chain. Enzyme kinetics appeared to be biphasic with a V(max) and apparent K(m) for the high-affinity site of 9.2 pmol/min/mg and 1.1 microm, respectively. the intrinsic metabolic clearance in human liver microsomes (V(max)/K(m), 8.4 ml/min/g protein) was comparable to that in rat and dog liver microsomes, but lower in mouse liver microsomes. Although the metabolic profile was identical in all subjects, a large quantitative variation in docetaxel biotransformation rates was found in a human liver microsome library, with a ratio of 8.9 in the highest:lowest biotransformation rates. Docetaxel biotransformation was correlated significantly (0.7698; P < 0.0001) with erythromycin N-demethylase activity, but not with aniline hydroxylase or debrisoquine 4-hydroxylase. It was inhibited, both in human hepatocytes and in liver microsomes, by typical CYP3A substrates and/or inhibitors such as erythromycin, ketoconazole, nifedipine, midazolam, and troleandomycin. Docetaxel metabolism was induced in vitro in human hepatocytes by dexamethasone and rifampicin, both classical CYP3A inducers. These data suggest a major role of liver cytochrome P450 isoenzymes of the CYP3A subfamily in docetaxel biotransformation in humans. Finally, some Vinca alkaloids and doxorubicin were shown to inhibit docetaxel metabolism in human hepatocytes and liver microsomes. These findings may have clinical implications and should be taken into account in the design of combination cancer chemotherapy regimens.

Animals↗
PubMed1996

Irinotecan (CPT-11) metabolites in human bile and urine.

A female patient was treated with irinotecan (CPT-11) for liver metastatic colon carcinoma. She had a percutaneous biliary catheter because of extrahepatic biliary obstruction. The patient was treated with CPT-11 for three courses at doses of 350 mg/m2 for the first course and 300 mg/m2 for the remaining courses, given as a 30-min i. v. infusion. Metabolism studies in bile and urine were performed by coupling high-performance liquid chromatography to electrospray mass spectrometry. Conventional spectra [liquid chromatography/mass spectrometry (LC/MS)] allowed on-line molecular mass determination of CPT-11 and its main metabolites, whereas structural information was obtained by tandem mass spectrometry (LC/MS/MS). At least 16 metabolites were detected in bile, while 8 of them were also detected in urine. Three compounds were identified as the parent drug, the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide. The major metabolic pathway consists in oxidations of the terminal piperidine ring of the CPT-11 side chain, which eventually results in the formation of a primary amine. Other metabolites result from oxidation of the camptothecin nucleus. Finally, decarboxylation of the carboxylate form of CPT-11 was also observed. Several metabolites result from combinations of these pathways. The structures of the identified metabolites indicate for the first time a major role of monooxygenases in the elimination of a camptothecin derivative in humans. This finding will allow better understanding of interindividual variability in pharmacokinetics and intestinal toxicity of CPT-11.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: Preclinical experience.

Docetaxel is a taxoid which is currently in phase II/III clinical trials in Europe, the US and Japan. It was found to promote tubulin assembly in microtubules and to inhibit their depolymerization. In vitro, the docetaxel concentrations required to reduce murine and human cell survival by 50% ranged from 4 to 35 ng/ml and the cytotoxic effects were greater on proliferating than on non-proliferating cells. It was also found to be cytotoxic on fresh human tumor biopsies. In vivo, the drug was found to be schedule independent. A total of 13/14 murine transplantable tumors were found very sensitive to i.v. docetaxel and complete regressions of advanced stage tumors were obtained. Activity was also observed in 15/16 human tumor xenografts in nude mice at an advanced stage. In combination studies, synergism was observed in vivo with 5-fluorouracil, cyclophosphamide and etoposide. Pharmacokinetic evaluation revealed linear pharmacokinetics in tumor-bearing mice. There was a good tumor retention with a 22 h elimination half-life. Plasma protein binding ranged from 76 to 89%. Preclinical toxicology evaluation of docetaxel included single-dose toxicity in rats, mice and dogs, 5-day toxicity in mice and dogs, intermittent-dose toxicity in rats, dogs and monkeys, genetic and reproductive toxicity, as well as investigation of the irritation and sensitization potential. The principal toxicities were hematopoietic (all species), gastrointestinal (dog, monkey) and neuromotor (mice). Dogs appeared to be the most sensitive species. The clinical entry dose of 5 mg/m2 was based on one-third of the 'toxic dose low' in dogs (15 mg/m2).

Animals↗
PubMed1993

Pharmacokinetics and metabolism of Taxotere (docetaxel).

The pharmacokinetics and metabolism of Taxotere have been studied after intravenous infusion in mice, dogs and cancer patients. Multiphasic disposition profiles have been observed with rapid initial tissue uptake and large distribution volumes. Hepatobiliary extraction is the major route of elimination, with similar metabolic pathways in all the species. In mice, both systemic and tumour exposures increased proportionately with the dose. In phase I studies, Taxotere pharmacokinetics were not dependent on the various administration schedules. After short intravenous infusions of 70-115 mg/m2 every 3 weeks, a three phase disposition profile was observed with a terminal half-life of 12 hours and a plasma clearance of 21 l/hr/m2. A limited sampling strategy has been designed and large scale prospective population pharmacokinetic/pharmacodynamic studies have been implemented in ongoing phase II studies.

Antineoplastic Agents, Phytogenic↗
PubMed1989

Clinical significance of a new isoform of serum alanine aminopeptidase; relationship with liver disease and alcohol consumption.

The potential clinical interest of a new isoform of alanine aminopeptidase (AAP) was examined using polyacrylamide gradient gel electrophoresis. This form, called F-AAP, is more proteolyzed than normal serum AAP. It appears to be associated with many liver diseases and is related to cytolysis, but also to elevated GGT levels. The F-AAP form was present in 52% of subjects treated with anticonvulsant drugs and in 64% of subjects consuming more than 44 g of alcohol per day. Analysis of F-AAP may be of interest in detecting effects of drugs and alcohol on the liver.

Adult↗
PubMed1988

Human aminopeptidases: a review of the literature.

The aminopeptidases constitute a group of enzymes with closely related activities. In clinical chemistry the analysis of the aminopeptidases and of their multiple forms in serum has for a long time been hindered by considerable confusion concerning their identification, and by a lack of characterization. This is in part due to the often large, and sometimes overlapping substrate specificities of the aminopeptidases. This paper reviews the biochemical properties of the different aminopeptidases, the specificities of the assays used for their analysis in serum, some aspects of their multiple forms--which are especially known to occur for alanine aminopeptidase (EC 3.4.11.2)--and the importance of the determination of aminopeptidases and their multiple forms in clinical chemistry.

Aminopeptidases↗
PubMed1988

Alanine aminopeptidase in serum: biological variations and reference limits.

We studied the effect of various factors on the biological variation of alanine aminopeptidase (AAP, EC 3.4.11.2) in serum in a population of 2178 apparently healthy subjects and in subjects taking specific drugs. To measure AAP, we used an automated assay, with alanyl-4-nitroanilide as substrate. AAP activity concentrations were significantly higher in males than in females in all age groups between 10 and 55 years. The highest mean AAP values were found for children between 10 and 14 years. In male heavy smokers, AAP values were 8% higher than in moderate or nonsmokers (P less than 0.001); in females, this effect was less pronounced. AAP concentrations were higher in subjects consuming over 44 g of ethanol a day than in those consuming less (P less than 0.01 for men, P less than 0.05 for women). The use of oral contraceptives increased AAP values by 12% (P less than 0.001). Hypolipidemic drugs caused lower values for AAP in men (P less than 0.001). Subjects showing induction of gamma-glutamyltransferase (EC 2.3.2.2) by anticonvulsant drugs had also higher AAP activities (by 23%). Taking these data into account, we established reference limits for AAP in serum.

Adolescent↗
PubMed1988

Micro-scale two-dimensional electrophoresis of alkaline phosphatase from serum.

Isoenzymes of alkaline phosphatase (EC 3.1.3.1) were separated by micro-scale two-dimensional electrophoresis, with isoelectric focusing in capillary gels in the first dimension and polyacrylamide gradient-gel electrophoresis in the second. The isoenzymes detected were identified by several treatments--e.g., incubation with sialidase, papain, Triton X-100, and wheat-germ agglutinin--and by comparison with alkaline phosphatase from liver microsomes. Liver and bone isoforms in normal sera showed overlapping isoelectric points but differed in molecular mass, estimated as 172 and 185 kDa, respectively. Sera of patients with liver disease showed several additional groups of alkaline phosphatase isoforms, two of which were found to consist of multi-molecular complexes. Others probably correspond to incompletely glycated enzyme proteins. A further isoform with a mass of about 250 kDa does not seem to correspond to any known isoform of alkaline phosphatase in serum. With this technique, we demonstrated intra- and interindividual variations of the placental alkaline phosphatase isoenzyme in pregnancy sera.

Adult↗
PubMed1987

[Macroenzymes in human plasma. 2. Macrogamma-glutamyltransferase, macroalanine aminopeptidase, macroalkaline phosphatase, macroaminotransferases and other macroenzymes].

The authors propose here the second part of the review concerning the plasma macroenzymes. Informations are given about the high-molecular mass forms of gamma-glutamyltransferase (GGT), alanine aminopeptidase (AAP), alkaline phosphatase (ALP), aminotransferase, acid phosphatase and glucose-6-phosphatase dehydrogenase. For almost all these enzymes, the presence of enzyme-immunoglobulins complexes may be observed in some plasma, but a specific immune character of these complexes has not always been proved. The membrane origin of GGT, AAP and ALP is responsible for the existence of special circulating macroforms: enzyme-lipoproteins associations due to the amphiphilic nature of some forms of these enzymes, and complexes between enzymes and membrane components. Although the knowledge about the structure of all these macroenzymes is increasing, the clinical interest to consider their existence because of the diagnostic uncertainties they may induce.

Acid Phosphatase↗
PubMed1987

[Macroenzymes in human plasma. 1: Macroamylase, macrocreatine kinase, macrolactate dehydrogenase].

The authors propose here a general review of the main macroenzymes described until now. In this first part, informations will be given about the high molecular forms of alpha amylase, creatine kinase (CK) and lactate dehydrogenase (LDH) found in human plasma. Except macro CK type 2 which can be related to the mitochondrial CK, these macroenzymes are the result of the formation of enzyme immunoglobulin complexes; their specific immune character has been demonstrated in some cases. The formation of such immune complexes between the enzyme protein and plasma immunoglobulins seems a rather common phenomenon although neither the mechanism involved nor the physiopathological significance are known since they have been observed in patients and healthy individuals. Nevertheless, it is important to recognize these macromolecular forms because of the diagnostic uncertainties they may induce during isoenzyme studies and even total enzyme activity measurement.

Antigen-Antibody Complex↗
PubMed1985

Quantitative measurement of plasma hemoglobin by second derivative spectrophotometry.

The development and validation of a second derivative spectrophotometric assay for hemoglobin in plasma is reported. Using the oxyhemoglobin absorbance peak at 578 nm, the method was found to be linear for standard samples in the range of 3-2,000 mg/l oxyhemoglobin. Because of one dilution step this range is doubled for plasma samples. Correlation with an enzymatic assay was excellent (r2 = 0.985). Within-run and between-run precision analysis showed CV values ranging from 0.5-6.5% for specified calculation conditions. Icteric or lipemic backgrounds did not influence the results. All calculations of derivative spectra were carried out for three different wavelength intervals. The largest interval (delta gamma = 6 nm) showed the best performance. The method is simple and rapid and it has been introduced successfully in our laboratory for routine clinical use.

Hemoglobins↗