Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency

Zurfluh M. R., Fiori L., Fiege B., Ozen I., Demirkol M., Gartner K. H., ...More

JOURNAL OF INHERITED METABOLIC DISEASE, vol.29, no.6, pp.725-731, 2006 (SCI-Expanded) identifier identifier identifier


The oral loading test with tetrahydrobiopterin (BH4) is used to discriminate between variants of hyper-phenylalaninaemia and to detect BH4-responsive patients. The outcome of the loading test depends on the genotype, dosage of BH4, and BH4 pharmacokinetics. A total of 71 patients with hyperphenylaianinaemia (mild to classic) were challenged with BH4 (20 mg/kg) according to different protocols (1 x 20 mg or 2 x 20 mu) and blood BH4 concentrations were measured in dried blood spots at different time points (T-0, T-2, T-4, T-8, T-12, T-14, T-32 and T-48h). Maximal BH4 concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH4 administration in 63 out of 7 1 patients. Eight patients presented with maximal BH4 concentrations similar to 44% higher at 8 h than at 4 h. After 24 h, BH4 blood concentrations dropped to 11% of maximal values. This profile was similar using different protocols. The following pharmacokinetic parameters were calculated for BH4 in blood: t(max) = 4h, AUC (T0-32) = 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 BH4 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 BH4 administration, while one was found to be a non-responder. Only 10/19 patients (53%) with Phe concentrations of 600-1200 mu mol/L responded to BH4 administration, and of the patients with the severe classical phenotype (blood Phe > 1200 mu mol/L) only 4 out of 17 patient responded. An additional 36 patients with mild hyperphenylalaninaemia (HPA) who underwent the combined loading test with Phe+BH4 were all responders. Slow responders and non-responders were found in all groups of HPA.