Hereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway (see Fig. 2).

This disorder is characterized by progressive liver failure, increased risk of hepatocellular carcinoma, coagulopathy, painful neurologic crises, and renal tubular dysfunction resulting in rickets. The clinical phenotype is variable. Most patients present before 6 months of age with the acute form of the disease. These children exhibit symptoms of acute liver failure, recurrent bleeding and have a high risk of mortality within the first year of life. In the subacute form, children present with symptoms between 6 and 12 months of age and have a less rapid progression of liver disease. In the chronic form, symptoms do not appear until after one year of age and these patients have a more gradual progression to liver failure. Patients with chronic HT-1 are at increased risk of developing hepatocellular carcinoma and progressive renal tubular dysfunction resulting in secondary hypophosphatemia and rickets. Patients with all forms of the disease are at risk of painful porphyria-like neurologic crises, which occur in 5-20% of patients per year as part of the natural history of the disorder. Dietary restriction of tyrosine and phenylalanine may improve liver and kidney function but does not prevent the progression of the disease. Liver transplant can correct most of the metabolic effects of the disorder except for the renal tubular dysfunction, which may be due to the local production of toxic metabolites in the kidney.

Figure 2. Biochemical pathway of tyrosine degradation and its association with porphyrin synthesis in HT-1.

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, Nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1

Pharmacokinetics and Drug Metabolism

Limited information exists on the metabolism, distribution, and excretion of Nitisinone in rats. Nitisinone was greater than 90% bioavailable following oral administration of the labeled compound in rats and was distributed to different organs, particularly the liver and kidney, where radioactivity remained for 7 days after administration. Nitisinone was biotransformed in rats and excreted via the urine.

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