Journal of Inherited Metabolic Disease

, Volume 29, Issue 6, pp 725–731

Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency

  • M. R. Zurflüh
  • L. Fiori
  • B. Fiege
  • I. Ozen
  • M. Demirkol
  • K. H. Gärtner
  • B. Thöny
  • M. Giovannini
  • N. Blau
Original Article

DOI: 10.1007/s10545-006-0425-6

Cite this article as:
Zurflüh, M.R., Fiori, L., Fiege, B. et al. J Inherit Metab Dis (2006) 29: 725. doi:10.1007/s10545-006-0425-6

Summary

The oral loading test with tetrahydrobiopterin (BH4) is used to discriminate between variants of hyperphenylalaninaemia 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 hyperphenylalaninaemia (mild to classic) were challenged with BH4 (20 mg/kg) according to different protocols (1 × 20 mg or 2 × 20 mg) and blood BH4 concentrations were measured in dried blood spots at different time points (T0, T2, T4, T8, T12, T24, T32 and T48 h). Maximal BH4 concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH4 administration in 63 out of 71 patients. Eight patients presented with maximal BH4 concentrations ∼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: tmax = 4 h, AUC (T0−32) = 370 nmol × h/g Hb, and t1/2 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 μmol/L responded to BH4 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+BH4 were all responders. Slow responders and non-responders were found in all groups of HPA.

Abbreviations

AUC

area under the curve

BH4

tetrahydrobiopterin

HPA

hyperphenylalaninaemia

PAH

phenylalanine hydroxylase

PKU

phenylketonuria

t1/2

half-life

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  • M. R. Zurflüh
    • 1
  • L. Fiori
    • 3
  • B. Fiege
    • 2
    • 3
  • I. Ozen
    • 4
  • M. Demirkol
    • 4
  • K. H. Gärtner
    • 1
  • B. Thöny
    • 1
  • M. Giovannini
    • 3
  • N. Blau
    • 1
  1. 1.Division of Clinical Chemistry and BiochemistryUniversity Children’s HospitalZurichSwitzerland
  2. 2.Division of Metabolism and Molecular PediatricsUniversity Children’s HospitalZurichSwitzerland
  3. 3.Ospedale San PaoloClinica PediatricaMilanoItaly
  4. 4.Istanbul Faculty of Medicine, Department of Nutrition and MetabolismChildren’s HospitalIstanbulTurkey

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