Effects of repeated intravenous administration of haem arginate upon hepatic metabolism of foreign compounds in rats and dogs.

Haem arginate is a new haem compound, recently introduced for the treatment of acute hepatic porphyrias. Porphyrias are characterized biochemically by decreased formation of haem due to defects in certain enzyme activities involved in the haem biosynthesis. Haem is essential for cell respiration and oxidative biotransformation. Hepatic drug metabolism, haem biosynthesis and catabolism were investigated after repeated intravenous administration of haem arginate in connection with toxicity studies. The daily doses of haem for rats were 4, 12 and 40 mg kg-1 and for dogs 3 and 9 mg kg-1 for 30 days and for 28 days, respectively. Hepatic microsomes were used in the assay of the following drug metabolizing enzymes: cytochrome P-450 and b5, aminopyrine N-demethylase, ethoxyresorufin O-deethylase and UDP-glucuronyl transferase. The assay of NADPH-cytochrome C-reductase and the enzymes reflecting synthesis and metabolism of haem in the liver (delta-aminolaevulinic acid synthase, delta-aminolaevulinic acid dehydratase, uroporphyrinogen I-synthase, uroporphyrinogen decarboxylase, haem synthase, haem oxygenase and biliverdin reductase) were performed from 20,000 g supernatants. The lowest dose administered to rats and dogs did not cause any significant changes compared to controls in the parameters measured. The highest doses significantly increased the activities of haem oxygenase and uroporphyrinogen I-synthase but decreased concentrations or activities of other enzymes, e.g. cytochrome P-450 and ethoxyresorufin O-deethylase. The results show that it is important to avoid overdosage of haem when restoration of mixed function oxygenase activity is needed.