Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats

ABSTRACT We evaluated the effect of hypothermia on the in vivo pharmacokinetics of midazolam (MDZ), with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with MDZ (which is metabolized mainly by CYP3A2) at 37, 32, or 28 °C. The Michaelis–Menten constant (Km) and maximum velocity (Vmax) of MDZ were estimated using the Michaelis–Menten equation. The Km of CYP3A2 MDZ remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32, or 28 °C by a heat lamp or ice pack, plasma concentrations of MDZ were higher, whereas those in the brain and liver were unchanged at 28 °C. Tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of MDZ in serum at 28 °C was half that at 37 °C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research