Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes.
OBJECTIVE
To screen the inhibitory effects of H1-antihistamines on hepatic bufuralol 1'-hydroxylation and on tolbutamide 4-methylhydroxylation in human liver microsomes.


METHODS
Bufuralol 1'-hydroxylation and tolbutamide 4-methylhydroxylation were used as index reactions for CYP2D6 and CYP2C9, respectively. The metabolites of both reactions were measured using high-performance liquid chromatography and were used as indicators of whether CYP2D6 or CYP2C9 activities were inhibited or unaffected by the agents.


RESULTS
All five H1-antihistamines studied showed a concentration-dependent inhibition of CYP2D6-mediated bufuralol 1'-hydroxylation with 50% inhibitory concentration (IC50) values of 32-109 microM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 microM and 88 microM, respectively. Tripelennamine, chlorpheniramine, and diphenhydramine showed no inhibitory effects on CYP2C9.


CONCLUSIONS
All five H1-antihistamines studied inhibited CYP2D6 markedly, but only cyclizine and promethazine inhibited CYP2C9 at concentrations above that usually seen in plasma. Promethazine and chlorpheniramine inhibited CYP2D6 at concentrations that are very close to their therapeutic plasma concentrations. Further studies in humans, especially in poor metabolizers of CYP2D6, will be required to confirm these findings.
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Nu
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Department of Medicine, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Zhang
Wen-Qi
WQ
Shockley
Dolores
D
Edeki
Timi
T
D001189:Aryl Hydrocarbon Hydroxylases; D002744:Chlorpheniramine / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism*; D011398:Promethazine / Q000494:pharmacology; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D014044:Tolbutamide / Q000378:metabolism
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D006634:Histamine H1 Antagonists; D002744:Chlorpheniramine; C010831:bufuralol; D014044:Tolbutamide; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D011398:Promethazine