AIMS: To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A. METHODS: Intravenous midazolam 2.5 mg or 2.5-8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1'-hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1'-hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose-normalized plasma midazolam concentrations (concentration/per dose). RESULTS: Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean +/- SD, 95% confidence level) in cancer (424 +/- 155, 61.3 ml min(-1); 1.21 +/- 0.46, 0.18 l kg(-1)) and noncancer (407 +/- 135, 57.1 ml min(-1); 1.15 +/- 0.33, 0.155 l kg(-1)) patients, respectively, were not different and comparable with published data. Clearance variability was 4-5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the 1-h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001. CONCLUSIONS: CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4-5-fold and were not different between groups. One to two-fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.
AIMS: To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A. METHODS: Intravenous midazolam 2.5 mg or 2.5-8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1'-hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1'-hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose-normalized plasma midazolam concentrations (concentration/per dose). RESULTS: Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean +/- SD, 95% confidence level) in cancer (424 +/- 155, 61.3 ml min(-1); 1.21 +/- 0.46, 0.18 l kg(-1)) and noncancer (407 +/- 135, 57.1 ml min(-1); 1.15 +/- 0.33, 0.155 l kg(-1)) patients, respectively, were not different and comparable with published data. Clearance variability was 4-5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the 1-h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001. CONCLUSIONS:CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4-5-fold and were not different between groups. One to two-fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.
Authors: K R Balson; D J Morgan; B H Richmond; M E McAlindon; S L Elliott; N D Yeomans Journal: J Gastroenterol Hepatol Date: 1996-12 Impact factor: 4.029
Authors: K E Thummel; D D Shen; T D Podoll; K L Kunze; W F Trager; C E Bacchi; C L Marsh; J P McVicar; D M Barr; J D Perkins Journal: J Pharmacol Exp Ther Date: 1994-10 Impact factor: 4.030
Authors: K E Thummel; D D Shen; T D Podoll; K L Kunze; W F Trager; P S Hartwell; V A Raisys; C L Marsh; J P McVicar; D M Barr Journal: J Pharmacol Exp Ther Date: 1994-10 Impact factor: 4.030
Authors: K E Thummel; D O'Shea; M F Paine; D D Shen; K L Kunze; J D Perkins; G R Wilkinson Journal: Clin Pharmacol Ther Date: 1996-05 Impact factor: 6.875
Authors: Rob ter Heine; Lisette Binkhorst; Anne Joy M de Graan; Peter de Bruijn; Jos H Beijnen; Ron H J Mathijssen; Alwin D R Huitema Journal: Br J Clin Pharmacol Date: 2014-09 Impact factor: 4.335