Table 1

Inhibition of CYP2C8 and CYP2C9 isoforms by trimethoprim and sulfamethoxazole in human liver microsomes and recombinant P450 isoforms and the predicted in vivo inhibition of the metabolism of coadministered CYP2C8 and CYP2C9 substrates by trimethoprim and sulfamethoxazole, respectively, from in vitro data

P450 IsoformHuman Liver MicrosomesKi(IC50)1-a, Type of InhibitionRecombinant P450 Isoforms IC501-aPredicted in vivo Inhibition I/(I+Ki)1-b
μM %
TrimethoprimCYP2C8 32 (54), competitive7580 (26)
SulfamethoxazoleCYP2C9271 (544), competitive45613 (24)
  • 1-a  Ki values are derived using nonlinear regression analysis; IC50 are calculated graphically (see Experimental Procedures for details).

  • 1-b  Inhibitor concentration (I) of trimethoprim (130 μM) and sulfamethoxazole (40 μM) around the metabolic enzymes were calculated using the liver/plasma partition ratios of 6.5 and 0.15 for trimethoprim and sulfamethoxazole (Craig and Kunin, 1973), respectively. The plasma concentrations of trimethoprim (20 μM) and sulfamethoxazole (250 μM) were adopted from Moore et al. (1996) and Dollery (1999). Data in the parentheses were calculated using unbound plasma concentrations of trimethoprim (11 μM) and sulfamethoxazole (85 μM), assuming that 55% of trimethoprim and 34% of sulfamethoxazole are unbound in plasma (Dollery, 1999) and that equal unbound concentrations are found in plasma and at the enzyme site.