Effects of heme arginate on cytochrome P450-mediated metabolism of drugs in patients with variegate porphyria and in healthy men.
We investigated the effects of heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without heme, a single infusion of heme arginate (3 mg/kg heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of heme on drug metabolism is P450 isozyme-specific.
Mustajoki
P
P
Third Department of Medicine, University of Helsinki, Finland.
Mustajoki
S
S
Rautio
A
A
Arvela
P
P
Pelkonen
O
O
D000328:Adult; D001120:Arginine / Q000494:pharmacology*; D002110:Caffeine / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006418:Heme / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects; D008012:Lidocaine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017094:Porphyrias, Hepatic / Q000201:enzymology / Q000378:metabolism*; D012016:Reference Values
D003374:Coumarins; D007527:Isoenzymes; D002110:Caffeine; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D001120:Arginine; D008012:Lidocaine; C030123:coumarin; C048849:heme arginate; D003647:Debrisoquin