Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolyase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In these patients, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity.
Since nitisinone inhibits catabolism
of tyrosine, use of this drug can result in elevated plasma levels of this amino acid. Treatment with nitisinone, therefore, requires restriction of the dietary intake of tyrosine and phenylalanine to prevent this toxicity.
Hereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway. This disorder is characterized by progressive liver failure, increased risk of hepatocellular carcinoma, coagulopathy, painful neurologic crises, and renal tubular dysfunction resulting in rickets.
EPAR of nitisinone.