European Journal of Clinical Pharmacology

, Volume 57, Issue 12, pp 847–851 | Cite as

Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes

  • Nu He
  • Wen-Qi Zhang
  • Dolores Shockley
  • Timi Edeki
Pharmacokinetics and Disposition

Abstract.

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 µM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 µM and 88 µM, respectively. Tripelennamine, chlorpheniramine, and diphenhydramine showed no inhibitory effects on CYP2C9. Conclusion: 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.

CYP2D6 CYP2C9 H1-antihistamines 

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Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Nu He
    • 1
  • Wen-Qi Zhang
    • 2
  • Dolores Shockley
    • 2
  • Timi Edeki
    • 1
  1. 1.Departments of Medicine and Pharmacology, Morehouse School of Medicine, 720 Westview Drive, S.W. Atlanta, GA 30310USA
  2. 2.Department of Pharmacology, Meharry Medical College, Nashville, TN 37208USA

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