Nitisinone decreases
homogentisic acid (HGA) in
Alkaptonuria (AKU) by inhibiting the
tyrosine metabolic pathway in humans. The effect of different daily doses of
nitisinone on circulating and 24 h urinary excretion of
phenylalanine (PA),
tyrosine (TYR), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (
HPLA) and HGA in patients with AKU was studied over a four week period. Forty AKU patients, randomised into five groups of eight patients, received doses of 1, 2, 4 or 8 mg of
nitisinone daily, or no drug (control). Metabolites were analysed by tandem mass spectrometry in 24 h urine and serum samples collected before and after
nitisinone. Serum metabolites were corrected for total body water and the sum of 24 hr urine plus total body water metabolites of PA, TYR, HPPA,
HPLA and HGA were determined.
Body weight and urine
urea were used to check on stability of diet and metabolism over the 4 weeks of study. The sum of quantities of urine metabolites (PA, TYR, HPPA,
HPLA and HGA) were similar pre- and post-
nitisinone. The sum of total body water metabolites were significantly higher post-
nitisinone (p < 0.0001) at all doses. Similarly, combined 24 hr urine:total body water ratios for all analytes were significantly higher post-
nitisinone, compared with pre-
nitisinone baseline for all doses (p = 0.0002 - p < 0.0001). Significantly higher concentrations of metabolites from the
tyrosine metabolic pathway were observed in a dose dependant manner following treatment with
nitisinone and we speculate that, for the first time, experimental evidence of the metabolite pool that would otherwise be directed towards pigment formation, has been unmasked.