Inhibition of debrisoquin clearance in perfused rat livers and inhibition of dextromethorphan metabolism in human liver microsomes by 4-hydroxydebrisoquin or other metabolites of debrisoquin.
Debrisoquin undergoes oxidative metabolism to 4-hydroxydebrisoquin, catalyzed by cytochrome CYP2D1 in rats and CYP2D6 in humans. Cytochrome CYP2D6 also plays a major role in dextromethorphan O-demethylation. In preliminary studies in perfused Lewis rat livers, we observed a difference in repeat clearance experiments using debrisoquin, but not dextromethorphan. To determine whether this change in clearance with time was due to the accumulation of 4-hydroxydebrisoquin, we sequentially used a recirculating and nonrecirculating perfusion system in the same liver perfusion experiment. We also studied the kinetics of dextromethorphan O-demethylation in microsomes prepared from human and rat livers in the presence and absence of 4-hydroxydebrisoquin. Results from the perfused rat liver experiments showed a drop in clearance from 3.27 +/- 0.57 ml/min (clearance 1) to 1.61 +/- 0.27 ml/min (clearance 2) (p less than 0.05 vs. clearance 1) during recirculation, but clearance returned to 3.21 +/- 0.46 ml/min (clearance 3, no significance vs. clearance 1) after a 30-min period of liver perfusion using a nonrecirculating system. There was significant accumulation of 4-hydroxydebrisoquin in the liver perfusate during recirculation, and concentrations fell when the nonrecirculating system was used. In microsomal studies, 4-hydroxydebrisoquin competitively inhibited dextromethorphan metabolism in human microsomes was 600 microM. These data suggest that: (a) 4-hydroxydebrisoquin and/or other metabolites of debrisoquin have an inhibitory effect on CYP2D1 and CYP2D6; (b) the active site of human CYP2D6 has different substrate specificity than the rat isozyme (CYP2D1) and/or that the pathways of metabolism of dextromethorphan are different in the Lewis rat and not primarily dependent on the activity of CYP2D1.
Jaruratanasirikul
S
S
Department of Medicine, Stanford University Medical Center, CA 94305-5113.
Cooper
A D
AD
Blaschke
T F
TF
D000818:Animals; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003647:Debrisoquin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003915:Dextromethorphan / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013379:Substrate Specificity
C012359:4-hydroxydebrisoquin; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin