Drug−drug Interaction between Losartan and Paclitaxel in Human Liver Microsomes with DifferentCYP2C8 Genotypes

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Abstract
The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of theCYP2C8*3 polymorphism.HLMs that contained theCYP2C8*1 homozygote (HL60) orCYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in theHL60 (p < 0.001) andHL54 (p < 0.01), respectively. When usingHL60, losartan and theCYP3A4‐selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, aCYP2C8‐selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed byCYP3A4 inHL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism inHL54, indicating that bothCYP2C8 andCYP3A4 play important roles in paclitaxel metabolism inHL54. These findings suggest that 50 μmol/L of losartan inhibits bothCYP2C8 andCYP3A4 inHLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.
Funding Information
  • Karolinska Institutet

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