Table 1

Nature of inhibition mechanism of three protease inhibitors on methadone and buprenorphine N-dealkylations

Protease Inhibitor[I] Plasma (μM)Cmax1-a μM (dose)t1/21-a (h)SubstrateType of InhibitionKi (μM)αPredicted % of Inhibition
Ritonavir1515.53.2BuprenorphineCompetitive0.02100%
Ritonavir(600 mg × 2)MethadoneCompetitive0.05100%
Indinavir4.7111.8BuprenorphineMixed-type0.83.385%
Indinavir(800 mg × 3)MethadoneNoncompetitive3No
Saquinavir0.0110.08613BuprenorphineCompetitive7No
Saquinavir(600 mg)MethadoneMixed-type1510No
  • Two microsomal preparations, Br67 and Br062, were used. The 1-ml incubation mixture consisted of variable concentrations of methadone or buprenorphine in 0.1 M phosphate buffer, pH 7.4, with 0.5 mg of microsomal proteins and variable amounts of protease inhibitor. After 5 min of preincubation at 37°C, reaction was started by 1 mM NADPH addition. The enzymatic reaction was stopped after 20 min at 37°C by addition of 100 μl of 2 M NaOH for methadone and by addition of 1 ml of 0.5 M phosphate buffer, pH 9.0, for buprenorphine metabolism.

  • 1-a Values from Barry et al., 1997; Lea and Faulds, 1996; Balani et al., 1996; Noble and Faulds, 1996.