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Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency
Author(s) -
Zurflüh M. R.,
Fiori L.,
Fiege B.,
Ozen I.,
Demirkol M.,
Gärtner K. H.,
Thöny B.,
Giovannini M.,
Blau N.
Publication year - 2006
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/s10545-006-0425-6
Subject(s) - tetrahydrobiopterin , pharmacokinetics , phenylalanine hydroxylase , phenylalanine , medicine , pharmacology , endocrinology , metabolic disease , human genetics , chemistry , biochemistry , amino acid , nitric oxide synthase , gene , nitric oxide
Summary The oral loading test with tetrahydrobiopterin (BH 4 ) is used to discriminate between variants of hyperphenylalaninaemia and to detect BH 4 ‐responsive patients. The outcome of the loading test depends on the genotype, dosage of BH 4 , and BH 4 pharmacokinetics. A total of 71 patients with hyperphenylalaninaemia (mild to classic) were challenged with BH 4 (20 mg/kg) according to different protocols (1 × 20 mg or 2 × 20 mg) and blood BH 4 concentrations were measured in dried blood spots at different time points (T 0 , T 2 , T 4 , T 8 , T 12 , T 24 , T 32 and T 48 h ). Maximal BH 4 concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH 4 administration in 63 out of 71 patients. Eight patients presented with maximal BH 4 concentrations ∼44% higher at 8 h than at 4 h. After 24 h, BH 4 blood concentrations dropped to 11% of maximal values. This profile was similar using different protocols. The following pharmacokinetic parameters were calculated for BH 4 in blood: t max = 4 h, AUC (T 0−32 ) = 370 nmol × h/g Hb, and t 1/2 for absorption (1.1 h), distribution (2.5 h), and elimination (46.0 h) phases. Maximal BH 4 blood concentrations were not significantly lower in non‐responders and there was no correlation between blood concentrations and responsiveness. Of mild PKU patients, 97% responded to BH 4 administration, while one was found to be a non‐responder. Only 10/19 patients (53%) with Phe concentrations of 600–1200 μmol/L responded to BH 4 administration, and of the patients with the severe classical phenotype (blood Phe > 1200 μmol/L) only 4 out of 17 patient responded. An additional 36 patients with mild hyperphenylalaninaemia (HPA) who underwent the combined loading test with Phe+BH 4 were all responders. Slow responders and non‐responders were found in all groups of HPA.