Abstract
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.
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