Published in:
01-02-2009 | BH4 and PKU
Pharmacokinetics of tetrahydrobiopterin following oral loadings with three single dosages in patients with phenylketonuria
Published in: Journal of Inherited Metabolic Disease | Issue 1/2009
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Background:
Tetrahydrobiopterin (BH4) loading has been performed for many years in patients detected by newborn screening for hyperphenylalaninaemia (HPA) to distinguish BH4 cofactor synthesis or recycling defects from phenylalanine hydroxylase (PAH)-deficient HPA. Previous studies have shown that the pharmacokinetics of BH4 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, BH4 loadings in single oral dosages of 10, 20 and 30 mg BH4/kg body weight (bw) were performed to assess BH4 responsiveness. As part of this study, levels of BH4 metabolites in dried blood spots were studied to provide information on the pharmacokinetics of BH4 following oral administration.
Results:
Levels of biopterin and pterin (B + P) increased significantly with increasing BH4 dose (p < 0.0001). Maximum B + P levels were reached 4 hours after application of BH4. There was no significant difference in BH4 pharmacokinetics between the three phenotypic groups of PKU. Male and female patients showed different levels of BH4 metabolites following 10 mg BH4/kg bw, but not following 20 and 30 mg BH4/kg bw. There was no relationship between age of patients and BH4 pharmacokinetics. There was no correlation between B + P levels and decrease in Phe level (p = 0.69).
Conclusion:
BH4 pharmacokinetics are variable between patients regarding absolute levels of BH4 metabolites reached after BH4 loading, but are similar regarding the interval to individual maximum B + P levels. Levels of B + P increase significantly with increasing BH4 doses. There is no correlation between B + P levels and decrease in Phe level.