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• W2004026573 abstract "We intended to clarify whether or not a patient with a high serum phenytoin concentration had a poor metabolic rate, possibly through possession of the CYP2C9*3 allele. However, since the patient underwent peripheral blood stem cell transplantation (PBSCT) about 2 months ago, the blood was altered from the recipient- to donor-type. Thus, we analysed the urine and succeeded in obtaining the genotype of the recipient. We report here that urine is a useful, non-invasive source of recipient DNA for genotype analysis to predict rate of drug metabolism in patients undergoing PBSCT.A 17-year-old man who underwent PBSCT to cure acute lymphoblastic leukaemia experienced convulsions, which seemed to be induced by tacrolimus. Tacrolimus was replaced by cyclosporin, and phenytoin (460 mg) was administered intravenously to prevent convulsions. The next day, phenytoin was reduced to 230 mg and maintained at this dose for 6 days. One week later, the patient was treated with oral phenytoin (100 mg, three times a day) in place of the injection. On day 3, after switching the route of administration, the trough concentration was monitored. Since, at 33.7 mg l−1, it was higher than the upper limit of therapeutic range (10–20 mg l−1), phenytoin treatment was discontinued. No blood samples before PBSCT remained. Therefore, after obtaining consent, we collected urine and current blood. To isolate genomic DNA, 20 ml of urine were centrifuged for 20 min at 1900 g, and the pellet was suspended in an aliquot of buffer ATL of QIAamp DNA Mini Kit (Qiagen GmbH, Hilden, Germany). DNA was then extracted according to the manufacturer's instructions. Since the enzymes responsible for metabolism of phenytoin were reported to be CYP2C9 [1, 2] and to a lesser extent CYP2C19 [3], we decided to determine the genotype of both CYP isoforms. The CYP2C19 genotype obtained from the urine (CYP2C19*1/*1) was clearly different from that of the blood (CYP2C19*1/*2) (Figure 1), indicating that urine is a useful source of genomic DNA derived from the patient's somatic cells. Unexpectedly, data obtained from the urine indicated that the patient possessed a homozygous wild-type of the CYP2C9 gene (Figure 1). This strongly suggested that the abnormal pharmacokinetics of phenytoin were not due to genetic polymorphism of CYP2C9 or CYP2C19. Reviewing current medications revealed that the patient had received fluconazole (400 mg day−1) for at least 1 month to prevent fungal infections. Fluconazole was known to be a potent inhibitor of CYP2C9 [4], and a drug interaction with phenytoin is found in a case report [5] and a clinical trial [6]. Although the clinical significance of fluconazole as an inhibitor of CYP2C19 is not well known, this drug strongly inhibits CYP2C19 in vitro[4]. The pharmacist, suspecting the occurrence of a drug–drug interaction, recommended halving the amount of phenytoin (50 mg, three times a day). Serum concentrations of phenytoin were measured for 10 days after the change in dosage. During this period, the concentration of phenytoin was stable in the therapeutic range of 16.9–17.9 mg l−1.Figure 1CYP2C9 and CYP2C19 genotypes analysed using urine and blood samples from the patient. Positive controls were loaded at the same time. The genotyping method used in this study to detect variant alleles of CYP2C9 and CYP2C19 were reported by Nasu et al. ...In this case, genotyping accelerated the discovery of a drug–drug interaction, and enabled exclusion of hereditary factors as a possible reason for unusual drug pharmacokinetics.Although the precise source of genomic DNA in the urine is unknown, it may be cell debris derived from renal collecting tubules and/or bladder. It should be stated that genotyping with urine may not succeed if the patient has pyuria, since the recipient DNA may be mixed with blood DNA produced by transplanted stem cells. Hair or buccal cells may be other possible sources. However, most patients undergoing PBSCT lose their hair due to pretreatment with alkylating agents. When collecting buccal cells, there is the risk of contamination by saliva containing leucocytes produced by donor stem cells. Taking these factors into account, urine may be the best sample from which to obtain original genomic DNA from patients who have undergone PBSCT or bone marrow/cord blood transplantation." @default.
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• W2004026573 date "2004-08-01" @default.
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• W2004026573 title "The use of urine to clarify the genotype of a patient with toxic phenytoin concentrations who had undergone peripheral blood stem cell transplantation" @default.
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• W2004026573 doi "https://doi.org/10.1111/j.1365-2125.2004.02123.x" @default.
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