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  • 1
    Electronic Resource
    Electronic Resource
    Association of aldehyde dehydrogenase with inheritance of NIDDM (1996)
    Springer
    Diabetologia 39 (1996), S. 1115-1118 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Aldehyde dehydrogenase ; chlorpropamide alcohol flushing test ; diabetes mellitus ; diabetic retinopathy ; ALDH2.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To investigate the influence of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) genotype on the clinical features of diabetes, 212 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) (154 males and 58 females aged 17–83 years; mean age 58.2 years) were investigated. Genotyping of ALDH2 was performed by the polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) method. The pattern of inheritance of diabetes and various clinical parameters was compared between active and inactive ALDH2 groups. Of the 212 subjects, 120 had active ALDH2 and 92 had inactive ALDH2. The percentage of patients with a diabetic mother was higher in the inactive ALDH2 group (32.6 %) than in the active ALDH2 group (19.2 %) (p 〈 0.05). The prevalence of proliferative retinopathy was lower in the inactive ALDH2 group than in the active ALDH2 group (p 〈 0.05). However, other clinical parameters showed no difference. We conclude that maternal inheritance of diabetes was common in the inactive ALDH2 group. The finding is suggestive of a relationship between alcohol intolerance and inheritance of diabetes. We speculate that the interaction between mitochondrial DNA and ALDH2 inactivity causes an increase of mitochondrial DNA mutations or deletions, thereby inducing the maternal inheritance of diabetes. The relationship of the ALDH2 genotype with proliferative retinopathy is interesting, because it resembles that of chlorpropamide alcohol flushing with severe diabetic retinopathy. The interaction of aldehyde dehydrogenase isoenzymes might have an aetiological role, since aldehyde dehydrogenase 1 plays an important part in oxidation of retinal to retinoic acid. However, the number of affected patients with proliferative retinopathy was small, hence, our result should be considered as a preliminary finding. [Diabetologia (1996) 39: 1115–1118]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400662
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  • 2
    Electronic Resource
    Electronic Resource
    CYP2C19 polymorphism effect on phenobarbitone (2000)
    Springer
    European journal of clinical pharmacology 55 (2000), S. 821-825 
    Details
    ISSN: 1432-1041
    Keywords: Key words Phenobarbitone ; CYP2C19 ; Genetic polymorphism ; Pharmacokinetics ; NONMEM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The aim of this study was to clarify the effect of genetic polymorphisms of CYP2C19 on the pharmacokinetics of phenobarbitone (PB) using a nonlinear mixed-effects model (NONMEM) analysis in Japanese adults with epilepsy. Methods: A total of 144 serum PB concentrations were obtained from 74 subjects treated with both PB and phenytoin but without valproic acid. All patients were classified into three groups by CYP2C19 genotyping: G1, G2 and G3 were homozygous for the wild type of CYP2C19 (*1/*1), heterozygous extensive metabolizers (EMs), (*1/*2 or *1/*3), and poor metabolizers (PMs), (*2/*2, *2/*3), respectively. All data were analyzed using NONMEM to estimate pharmacokinetic parameters of PB with respect to the CYP2C19 genotype. Results: Thirty-three patients belonged to G1 (44.6%), 35 to G2 (47.3%), and 6 to G3 (8.1%). The total clearance (CL) of PB significantly decreased by 18.8% in PMs (G3) relative to EMs (G1 and G2). The CL tended to be lower in G2 than in G1. Conclusion: In this study, we first demonstrated the effect of the CYP2C19 polymorphism on pharmacokinetics of PB by genotyping. The contribution of other metabolic enzymes in the metabolism of PB in humans remains to be elucidated; however, it appears that the disposition of PB is mediated in part by this enzyme. The estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050703
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  • 3
    Electronic Resource
    Electronic Resource
    Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9 * 3 allele (2000)
    Springer
    European journal of clinical pharmacology 56 (2000), S. 65-68 
    Details
    ISSN: 1432-1041
    Keywords: Key words CYP2C9 ; Genetic polymorphism ; Diclofenac
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug. Methods: A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/*1, n=6) and heterozygotes for the Leu359 variant (CYP2C9*1/*3, n=6). Results: For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/*1 and CYP2C9*1/*3 subjects, respectively (mean ± SD): apparent oral clearance (ml/kg/h) 355.8 ± 56.9 and 484.4 ± 155.3; area under plasma concentration–time curve (μg h/ml) 2.7 ± 0.7 and 1.9 ± 0.6. The formation clearance of 4′-hydroxydiclofenac (ml/kg/h) was 63.6 ± 19.1 in the CYP2C9*1/*1 subjects compared with 75.9 ± 27.6 in the CYP2C9*1/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4′-hydroxydiclofenac between the two genotype groups. Conclusion: Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050722
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