Grapefruit juice inhibits CYP2A6 and nicotine metabolism

Background/Aims Grapefruit juice is a strong inhibitor of CYP3A4 leading to clinically important interactions. The aim was to study the effect of grapefruit juice on the metabolism of nicotine, primarily a CYP2A6 substrate. Methods 10 volunteers were given 2 mg oral dose of deuterium‐labeled nicotine on three occasions together with 1 L of water, grapefruit juice or half‐strength grapefruit juice in randomized order. Nicotine and metabolites were analyzed in plasma and urine for 8 hours. Results Grapefruit juice inhibited the formation of cotinine from nicotine (AUC COT 0–8hr 6807 vs. 7805 vs. 8007 min*ng/ml, grapefruit juice, diluted grapefruit juice, and water, respectively, p< 0.05). T max of cotinine was delayed, and C max lower with grapefruit juice than with water (T max 216 vs. 159 vs. 147 min, p< 0.05, C max 18 vs. 21 vs. 22 ng/ml, p< 0.05). Grapefruit juice increased renal clearance of nicotine compared to water (231 vs. 123 ml/min, p< 0.05). Other pharmacokinetic parameters of nicotine were not affected. Conclusions Grapefruit juice inhibits the metabolism of nicotine to cotinine, a pathway mediated by CYP2A6. The inhibition is modest, and the effect on total nicotine clearance was offset by the increase in the renal clearance of nicotine. However, the inhibition of CYP2A6 by grapefruit juice may be of clinical significance with other drugs metabolized by CYP2A6. Clinical Pharmacology & Therapeutics (2005) 77 , P75–P75; doi: 10.1016/j.clpt.2004.12.178