Estimation of possible drug interactions that could be caused by montelukast on CYP2C8-cleared drugs
Values used for montelukast include: D = 10 mg; Fa = 0.62; ka = 0.008/min; fu = 0.01; Cmax = 603 ng/ml = 1.0 μM (Zhao et al., 1997); Ki = 0.0092 μM. The fraction of the affected drug metabolized by CYP2C8 is assumed to be unity in the expression. The estimate for Fa = 0.62 was made from the observation that clearance after intravenous administration was reported at 0.7 ml/min/kg (Cheng et al., 1996); hence, hepatic extraction is less than 5%, and oral bioavailability is 62%. The estimate for ka was made from the expression Tmax = (ln(ka/kel))/(ka–kel) in which kel was calculated from the reported t1/2 and Tmax values of 4.7 h and 3.5 h, respectively (Cheng et al., 1996).
In Vivo Inhibitor Concentration Available to the Enzyme | Equation Used to Estimate the in Vivo Inhibitor Concentration ([I]in vivo) Available to the Enzyme | Magnitude of Drug Interaction (Fold Increase in Exposure)  |
|---|---|---|
| Systemic total Cmax | [I]in vivo = Cmax | 112 |
| Systemic free Cmax | [I]in vivo = fu · Cmax | 2.1 |
| Estimated total portal Cmax | [I]in vivo = Cmax + ka · Fa · D/Qh | 119 |
| Estimated free portal Cmax | [I]in vivo = fu · (Cmax + ka · Fa · D/Qh) | 2.2 |
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AUC, area under the curve.