Description
Nitisinone was originally developed as a pesticide and then launched as an adjunct to
dietary restriction of tyrosine and phenylalanine for the treatment of hereditary
tyrosinaemia type I. In this inborn error of metabolism, fatal liver disease results either from
liver failure during infancy or early childhood or from development of hepatocellular
carcinoma during childhood or adolescence. This is caused by accumulation of toxic
metabolites due to deficiency of fumarylacetoacetase, the last enzyme of the tyrosine
catabolic pathway. Nitisinone, which acts as an inhibitor of the 4-hydroxyphenylpyruvate
dioxygenase, prevents the formation of toxic metabolites such as succinylacetoacetate in
the liver. Administration of a single dose of nitisinone in mice showed a rapid, significant
and persistent inhibition of 4-hydroxyphenylpyruvate dioxygenase. In a murine model of
tyrosinaemia type I, administration of nitisinone abolished acute liver failure. Additional
dietary tyrosine restriction in the same model on long term follow-up (> 2 years) showed
complete correction of liver function tests and succinylacetone levels, and cancer-free
survival improvements when compared to historical controls. In healthy volunteers,
nitisinone was well tolerated, peak plasma concentrations were rapidly attained following a
single dose of 1 mglkg and the half-life time was approximately 54 h. Following the
administration of nitisinone (1 mg/kg), the concentrations of tyrosine in plasma increased,
were still 8 times those of background at 14 days after dosing, but had returned to
background levels within 2 months of the second dose. Elevated tyrosine levels are a
potential risk of cornea1 opacities. No treatment related comeal lesions were seen after
administration of high dose of nitisinone in mice. In children diagnosed when they were
less than 2 months old, when nitisinone treatment was combined with a restricted diet, the
four-year survival rate was 88%, compared to 29% from historical data of children treated
with restricted diet alone. So, there is some clear evidence that nitisinone treatment
associated with restricted diet can reduce the risk of early hepatocellular carcinoma when
started before two years of age. On the contrary, in patients with late start of nitisinone
treatment there is a considerable risk of liver malignancy. Even if 10% of patients have not
clinically responded to nitisinone, studies have shown that oral nitisinone treatment plus
dietary restriction has greatly improved the survival of patients and reduced the need of
liver transplantation during early childhood.
Uses
Nitisinone is a herbicidal triketone that inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme involved in plastoquinone biosynthesis in plants and in tyrosine catabolism in mammals. It is u
sed in treatment of inherited tyrosinemia type I.
Biochem/physiol Actions
Nitisinone is a competitive inhibitor that reversibly inhibits 4-Hydroxyphenylpyruvate oxidase (dioxygenase). Nitisinone is used in the treatment of hereditary tyrosinemia type 1, where it blocks the degradation of tyrosine into harmful substances.
