title: Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency.
abstract: 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 x 20 mg or 2 x 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 approximately 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 x 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 mumol/L responded to BH(4) administration, and of the patients with the severe classical phenotype (blood Phe > 1200 mumol/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.
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital, Zurich, Switzerland.
authors.forename: M R
authors.initials: MR
authors.lastname: Zurflüh
authors.forename: L
authors.initials: L
authors.lastname: Fiori
authors.forename: B
authors.initials: B
authors.lastname: Fiege
authors.forename: I
authors.initials: I
authors.lastname: Ozen
authors.forename: M
authors.initials: M
authors.lastname: Demirkol
authors.forename: K H
authors.initials: KH
authors.lastname: Gärtner
authors.forename: B
authors.initials: B
authors.lastname: Thöny
authors.forename: M
authors.initials: M
authors.lastname: Giovannini
authors.forename: N
authors.initials: N
authors.lastname: Blau
mesh_terms: D000284:Administration, Oral; D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000201:enzymology; D019540:Area Under Curve; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005838:Genotype; D006801:Humans; D007700:Kinetics; D010641:Phenotype; D010649:Phenylalanine / Q000737:chemistry; D010651:Phenylalanine Hydroxylase / Q000172:deficiency*; D013997:Time Factors
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin