Effect of diethyldithiocarbamate (DDC) and ticlopidine on CYP1A2 activity and caffeine metabolism: an in vitro comparative study with human cDNA-expressed CYP1A2 and liver microsomes.
The aim of the present study was to test the effect of diethyldithiocarbamate (DDC), which is regarded as a cytochrome P450 (CYP) CYP2A6 and CYP2E1 inhibitor, and ticlopidine, an efficient CYP2B6, CYP2C19 and CYP2D6 inhibitor, on the activity of human CYP1A2 and the metabolism of caffeine (1-N-, 3-N- and 7-N-demethylation, and C-8-hydroxylation). The experiment was carried out in vitro using human cDNA-expressed CYP1A2 (Supersomes) and human pooled liver microsomes. The effects of DDC and ticlopidine were compared to those of furafylline (a strong CYP1A2 inhibitor). A comparative in vitro study provides clear evidence that ticlopidine and DDC, applied at concentrations that inhibit the above-mentioned CYP isoforms, potently (as compared to furafylline) inhibit human CYP1A2 and caffeine metabolism, in particular 1-N- and 3-N-demethylation.
Kot
Marta
M
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Daniel
Władysława A
WA
D002110:Caffeine / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018076:DNA, Complementary; D004050:Ditiocarb / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013988:Ticlopidine / Q000494:pharmacology*
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D002110:Caffeine; D004050:Ditiocarb; D013806:Theophylline; C050131:furafylline; D019388:Cytochrome P-450 CYP1A2; D013988:Ticlopidine