Effect of age, gender, and obesity on midazolam kinetics

The effects of age, sex, and obesity on the kinetics of single intravenous (iv) and oral doses of midazolam were evaluated in healthy volunteers who received 2.5-5 mg of iv midazolam on one occasion and 5-10 mg orally on another. Kinetics were determined from multiple plasma midazolam concentrations measured during 24 h after dosage. Midazolam elimination half-life (t(1/2)) after iv dosage was significantly prolonged in elderly (aged 60-74 yr) versus young (24-33 yr) males (5.6 vs. 2.1 hours, P <0.01) and total clearance was significantly reduced (4.4 vs. 7.8 ml·min^-1·kg^-1, P <0.01), leading to increased systemic availability of the oral dose (50% vs. 41%, P <0.05). However total volume of distribution calculated by the area method (V(d)) (1.6 vs. 1.3 l/kg) and protein binding (3.5 vs. 3.4% unbound) did not differ between groups. Among women there were no significant differences between elderly (64-79 yr) and young (23-37 yr) volunteers in t(1/2) (4.0 vs. 2.6 h), clearance (7.5 vs. 9.4 ml·min^-1·kg^-1), V(d) (2.1 vs. 2.0 l/kg), protein binding (3.7% vs. 3.7% unbound), or oral bioavailability (38% vs. 36%). In obese volunteers (mean weight 117 kg; 173% of ideal weight) versus control subjects of normal weight (66 kg, 95% of ideal weight) matched for age, sex, and smoking habits, midazolam V(d) was increased significantly (311 vs. 114 l, P <0.001). V(d) was greater in the obese subjects even after correction for total weight (2.7 vs. 1.7 l/kg, P <0.001), indicating disproportionate distribution of midazolam into adipose weight. Since clearance was not different between groups (472 vs. 530 ml/min), the prolonged t(1/2) in obese subjects (8.4 vs. 2.7, P <0.001) was due to the increased V(d). The clinical consequences of age- and obesity-related changes in midazolam kinetics will depend on the circumstances of administration.