Effects of feeding on the disposition of lorazepam and diazepam

Abstract

The effects of feeding on drug disposition were investigated using two common benzodiazepines, lorazepam and diazepam, as in vivo probes for drugs which are metabolized by direct glucuronide conjugation, and oxidative metabolism, respectively. The effects of feeding on lorazepam disposition were examined in insulin-dependent diabetes mellitus (IDDM) patients. A tightly-controlled ten-part study in four patients showed lorazepam clearance was significantly lower in euglycemic conditions with low levels of peripheral glucose matched with low insulin infusion rates than in studies with high levels of intragastric glucose with low (hyperglycemia) and high (euglycemia) insulin levels. This suggests that co-substrate availability may be a rate-limiting step in hepatic glucuronidation in man. Renal clearance of lorazepam glucuronide exhibited a similar pattern, suggesting that renal secretion is depressed in a low-energy state. No dose-dependent insulin response, or effect of insulin species was observed for any studied lorazepam parameter. High levels of insulin significantly depressed urine production in IDDM patients. Glucagon had no effect on lorazepam disposition. A study in ten IDDM patients indicated that insulin species influences lorazepam glucuronidation; however, this could not be substantiated in a small crossover study with three IDDM patients, or in the ten-part study. An animal model of enterohepatic circulation (EHC) of lorazepam was developed in the dog. Interruption of EHC resulted in lower plasma lorazepam concentrations, increased lorazepam clearance rates, and decreased volume of distribution. Lorazepam and lorazepam glucuronide concentrations were 10-100 fold greater in bile than in plasma, suggesting a pronounced biliary secretion. These data suggest that the dog model may be useful in studying EHC. The effects of feeding on diazepam disposition showed that post-prandial diazepam peaks are not due to EHC. Feeding caused a decrease in diazepam free fraction, suggesting that the peaks are the result of changes in plasma protein binding. Perturbation of plasma protein binding with heparin and fat emulsion were in agreement with this conclusion. Concentrations of unbound diazepam increased following meals, suggesting that decreased hepatic metabolism, and possibly redistribution from tissues may also play a role in the mechanism of postprandial diazepam peaks.