Prediction of the increase in midazolam AUC by macrolides using the steady-state enzyme level
Predicted AUC Ratioa | Reported | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | [I] |
Imaxb |
Imax,uc |
Iin,ud | AUC Ratio (mean ± S.D.) | Reference | ||||||||||
| kdeg (min-1)
|
0.0005
|
0.00033
|
0.0005
|
0.00033
|
0.0005
|
0.00033
| ||||||||||
| Erythromycin | 500 mg t.i.d. for 6 days | 11.9 | 17.6 | 3.2 | 4.3 | 4.6 | 6.5 | 4.4 ± 2.4 | Olkkola et al., 1993 | |||||||
| 500 mg t.i.d. for 5 days | 11.9 | 17.6 | 3.2 | 4.3 | 4.6 | 6.5 | 3.8 ± 2.4 | Zimmermann et al., 1996 | ||||||||
| Clarithromycin | 500 mg b.i.d. for 7 days | 4.9 | 6.8 | 2.1 | 2.7 | 6.1 | 8.7 | 7.0 ± 4.2 | Gorski et al., 1998 | |||||||
| 250 mg b.i.d. for 5 days | 3.0 | 4.0 | 1.6 | 1.9 | 3.6 | 5.0 | 3.6 ± 1.7 | Yeates et al., 1996 | ||||||||
| Azithromycin | 500 mg o.d. for 3 days | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.1 | 1.3 ± 0.9 | Zimmermann et al., 1996 | |||||||
|
|
500 mg o.d. for 3 days
|
|
1.0
|
1.0
|
1.0
|
1.0
|
1.0
|
1.1
|
1.2 ± 0.7
|
Yeates et al., 1996
| ||||||
↵ a Predicted AUC ratio = (kdeg + kinact × [I]/(K′app + [I]))/kdeg using K′app and kinact for the inhibition of midazolam α-hydroxylation by human liver microsomes. Imax, Imax,u or Iin,u for [I].
↵ b Imax, maximum concentration of inhibitor in the systemic blood.
↵ c Imax,u, maximum unbound concentration of inhibitor in the systemic blood. Imax,u = Imax × fu where fu is unbound fraction.
↵ d Iin,u, unbound concentration of inhibitor at the inlet to the liver. Iin,u = (Imax + ka D Fa/Q) × fu where ka is absorption rate constant, D is dose, Fa is fraction absorbed, and Q is hepatic blood flow.