Rapid clearance of supplemented tetrahydrobiopterin is driven by high-capacity transporters in the kidney.

Abstract Tetrahydrobiopterin (BH 4 ) is an essential cofactor of aromatic amino acid hydroxylases and NO synthase. Supplementation of BH 4 potentially targets cardiovascular dysfunction as well as inherited BH 4 deficiencies and BH 4 -responsive phenylketonuria. However, the high cost/effect ratio of the recommended daily dose of BH 4 supplementation acts against further popularization of this therapy. The aim of this study was to attenuate urinary excretion with the intention of improving efficacy of BH 4 supplementation. The rapid excretion of BH 4 in the urine was confirmed to be the major route of supplemented BH 4 loss. In addition to glomerular filtration into the urine, a dominant rapid exclusion by renal secretion was observed in rats (T (1/2)  = 16 min) when the plasma BH 4 was higher than about 1 nmol/mL (more than10 times higher than normal), due to BH 4 supplementation. The rapidity of the process was slowed by prior administration of cyclosporin A, a representative anti-excretory drug, and the excretion decelerated to a moderate rate (T (1/2)  = 53 min). By the combined administration of BH 4 plus cyclosporin A, the blood BH 4 levels were dramatically elevated. It was hypothesized that the drug interfered with kidney excretion of BH 4 rather than by attenuating organ tissue distribution by inhibiting biopterin uptake from the plasma. Consistent with this hypothesis, biopterin levels after BH 4 administration were elevated in major organs in the presence of anti-excretory drugs without notable change in their BH 4 fraction which was consistently 95% or higher regardless of combined administration with the drugs. Targeting these putative transporters would be a promising approach for improving the efficiency of BH 4 supplementation therapy.