We hypothesized that concomitant administration of diclofenac or disulfiram would not affect the oxidative metabolism of quinidine but that grapefruit juice, itraconazole and erythromycin indeed would inhibit the oxidative metabolism of quinidine, albeit by different orders of magnitude. discussed in detail 7-Methylguanine by Watkins [5] and Kivisto CYP3A4 assay. Quinidine, a class 1A antiarrythmic, is metabolized primarily by CYP3A4 [7]. Studies of human liver microsomes and yeast recombinant P450 expression systems have shown that the formation of the (3S)-3-hydroxymetabolite is mediated almost exclusively by CYP3A4 [8]. We hypothesize following a low oral single dose that the 3-hydroxylation of quinidine may serve as an biomarker reaction for CYP3A4 activity. This study is one of a series of systematic interaction studies, which address the specificity of quinidine for the CYP3A4 enzyme studies, we chose diclofenac as a putative competitive inhibitor of CYP2C9. Diclofenac is a substate with high affinity for Rabbit polyclonal to Caspase 7 this enzyme [11], and has been shown 7-Methylguanine to inhibit the metabolism of other CYP2C9 substrates [12]. The reductive product of disulfiram, diethylthiocarbamate, is a well documented potent inhibitor of CYP2E1 [13, 14]. Grapefruit juice is an inhibitor of intestinal CYP3A4 [15], itraconazole is a potent inhibitor of CYP3A4 [16, 17], and erythromycin also inhibits CYP3A4 [18]. We hypothesized that concomitant administration of diclofenac or disulfiram would not affect the oxidative metabolism of quinidine but that grapefruit juice, itraconazole and erythromycin indeed would inhibit the oxidative metabolism of quinidine, albeit by different orders of magnitude. The purpose of the present study is to confirm that the 3-hydroxylation of quinidine is mediated by CYP3A4 time curve. Statistical analyses Data are presented as median and range. Statistical test values are Hodges-Lehmann estimates of median differences with exact 95% confidence intervals. Inter-group comparison was made by the median test. Differences were considered statistically significant when the 95% confidence intervals excluded zero. Statistical analyses were performed using the software packages SPSS 7.5 for Windows (SPSS Inc., USA) and StatXact 3 (Cytel Software Corporation, USA). Results All volunteers completed the study. No side-effects were reported during administration of diclofenac. During administration of disulfiram, one volunteer had intermittent diarrhoea, and another volunteer complained of slight abdominal 7-Methylguanine discomfort. Side-effects during administration of itraconazole were nausea (one subject) and intermittent headache (one subject). Side-effects during administration of erythromycin was abdominal discomfort (one subject), while no side-effects were seen during administration of grapefruit juice. All control laboratory tests were within normal values. Six hours after administration of tolbutamide blood glucose concentrations were within the range of 2.6C5.9 mm, without any subjective or objective signs of hypoglycaemia, in all subjects. The only other side-effects noted were slight degrees of headache and irritability due to abstinence from caffeine. The study results with the pharmacokinetic parameters of quinidine and the biomarker reactions are summarized in Tables 1 and 2. Table 1 Quinidine (Q) pharmacokinetic parameters in 30 healthy young male volunteers, following a 200 mg single oral dose 7-Methylguanine with and without concomitant administration of diclofenac (Dic, studies, in which up to 23% of the quinidine and [13, 14, 27], a finding supported by our data as disulfiram did not affect any of the other marker reactions. An inhibitory effect of disufiram on the metabolism of caffeine as found by Beach [28], could not be confirmed here. The effects of itraconazole on the total clearance, renal clearance, partial clearances by 3-hydroxy-lation and CYP3A4 inhibition marker reaction of CYP3A4 activity. Acknowledgments This study was supported by grants from the Danish Medical Research 7-Methylguanine Council (Reference number 12-9206). The technical assistance of Mrs Birgitte Damby, Mrs Annnelize Casa and Mss Susanne J?rgensen is appreciated..