Activities of Cytochrome P450 1A2, N‐acetyltransferase 2, Xanthine oxidase, and Cytochrome P450 2D6 are Unaltered in Children with Cystic Fibrosis

Abstract

The activities of hepatic cytochrome P450 (CYP) 1A2, N-acetyltransferase 2 (NAT-2), xanthine oxidase (XO), and CYP2D6 were evaluated in 12 young children (aged 3-8 years) with mild cystic fibrosis (CF) and 12 age-matched healthy control subjects by use of standard caffeine and dextromethorphan phenotyping methods. Subjects were given 4 oz of Coca-Cola (approximately 35 mg caffeine) (The Coca-Cola Company, Atlanta, Ga) and a single 0.5-mg/kg dose of dextromethorphan. Urine was collected for 8 hours after biomarker administration, and enzyme activity was assessed by use of previously validated caffeine and dextromethorphan molar ratios. CYP2D6 genotyping was also performed in 10 of 12 subjects with CF and 11 of 12 control subjects. There were no significant differences in the urinary molar ratios for any of the enzyme systems evaluated. These data suggest that CF does not alter the activities of CYP1A2, NAT-2, XO, and CYP2D6. Altered biotransformation of drugs in this patient population is likely enzyme- and isoform-specific and thus is apparent for only selected compounds that are substrates for enzymes other than CYP1A2, NAT-2, XO, and CYP2D6.

The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype

“…CYP2D6 activity was determined using DM as the phenotyping probe, as described previously for each of the study cohorts. 1,10,18,23,24 Urine analysis was performed at two study sites, Morehouse School of Medicine and Children's Mercy Hospital. The method currently employed is described in detail by Abdel-Rahman et al, 31 with the high pressure liquid chromatography (HPLC) analysis subsequently modified as described by Blake et al 10 In essence, the urinary concentrations of DM and its O-demethylated metabolite, dextrorphan (DX), were determined by reversed-phase HPLC with fluorescence detection.…”

“…The second adult cohort comprises African‐American adults ( n =210) and represents a subset of that described earlier 1 . The third cohort represents primarily Caucasian and African‐American pediatric patients ( n =88), in which CYP2D6 activity appeared unaffected by disease or treatment, i.e ., sleep apnea, 23 cystic fibrosis, 24 and growth hormone deficiency 25 . The fourth ethnically mixed cohort includes 95 infants phenotyped at 12 months of age, at which time the recovery of DM and its three major metabolites was comparable to that observed in older pediatric and adult subjects 10 .…”

“…CYP2D6 phenotyping with DM . CYP2D6 activity was determined using DM as the phenotyping probe, as described previously for each of the study cohorts 1 , 10 , 18 , 23 , 24 . Urine analysis was performed at two study sites, Morehouse School of Medicine and Children's Mercy Hospital.…”

Reduced Activities of Cytochrome P450 1A2 and Xanthine Oxidase in Children With Growth Hormone Deficiency

“…Given the lack of difference between controls with and without CF (8), ratios for these groups were combined. Demographics and probe substrate doses are presented in Table 1.…”

“…Molar ratios were compared using the Mann Whitney test. Given the lack of difference between controls with and without CF (8), ratios for these groups were combined. The relation between age and enzyme activity was explored graphically and statistically (Spearman correlation coefficient).…”