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Pharmacokinetics of tetrahydrobiopterin following oral loadings with three single dosages in patients with phenylketonuria
Author(s) -
Gramer G.,
Garbade S. F.,
Blau N.,
Lindner M.
Publication year - 2009
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-008-0955-1
Subject(s) - tetrahydrobiopterin , hyperphenylalaninemia , pharmacokinetics , phenylalanine hydroxylase , phenylalanine , dose , pterin , biopterin , medicine , endocrinology , oral administration , phenylketonurias , chemistry , pharmacology , biochemistry , cofactor , enzyme , amino acid , nitric oxide synthase , nitric oxide
Summary Background: Tetrahydrobiopterin (BH 4 ) loading has been performed for many years in patients detected by newborn screening for hyperphenylalaninaemia (HPA) to distinguish BH 4 cofactor synthesis or recycling defects from phenylalanine hydroxylase (PAH)‐deficient HPA. Previous studies have shown that the pharmacokinetics of BH 4 shows high intra‐individual and inter‐individual variability. Methods: Seventeen adult patients with PAH‐deficient HPA were classified in one of three phenotypic groups (mild, moderate, classical PKU) according to their response to a standardized protein loading test. Genotype information was available for all participants. In a randomized controlled double‐blind design, BH 4 loadings in single oral dosages of 10, 20 and 30 mg BH 4 /kg body weight (bw) were performed to assess BH 4 responsiveness. As part of this study, levels of BH 4 metabolites in dried blood spots were studied to provide information on the pharmacokinetics of BH 4 following oral administration. Results: Levels of biopterin and pterin (B + P) increased significantly with increasing BH 4 dose ( p < 0.0001). Maximum B + P levels were reached 4 hours after application of BH 4 . There was no significant difference in BH 4 pharmacokinetics between the three phenotypic groups of PKU. Male and female patients showed different levels of BH 4 metabolites following 10 mg BH 4 /kg bw, but not following 20 and 30 mg BH 4 /kg bw. There was no relationship between age of patients and BH 4 pharmacokinetics. There was no correlation between B + P levels and decrease in Phe level ( p = 0.69). Conclusion: BH 4 pharmacokinetics are variable between patients regarding absolute levels of BH 4 metabolites reached after BH 4 loading, but are similar regarding the interval to individual maximum B + P levels. Levels of B + P increase significantly with increasing BH 4 doses. There is no correlation between B + P levels and decrease in Phe level.