Muscle Distribution of the Neuromuscular Blocker gallamine Using Microdialysis

Abstract

Measurement of drug concentrations in target tissue has the potential to provide insight into the pharmacokinetics and pharmacodynamics of a drug. In this study, the distribution of the neuromuscular blocker, gallamine, into muscle tissue was investigated in urethane‐anesthetized rats after an intravenous bolus dose (6 mg/kg). Microdialysis sampling was used to continuously determine gallamine concentrations in muscle interstitial fluid (MIF). In vivo microdialysis recovery of gallamine was determined as the relative loss of gallamine from the perfusate into muscle tissue after perfusion with gallamine (2 μg/mL). Recovery was determined in each rat before the pharmacokinetic studies. Terminal muscle sampling followed by homogenization was also performed to examine gallamine distribution within muscle tissue. All samples were assayed for gallamine using a validated high‐performance liquid chromatography assay. Gallamine was rapidly distributed into MIF with a MIF–plasma partition coefficient of 0.9 ± 0.1 (n = 6). By contrast, the estimated gallamine concentration in muscle tissue homogenate was only 23 ± 5% (n = 5) of the concentration in MIF as estimated by microdialysis sampling at the terminal sampling time. These findings suggest that gallamine is not distributed uniformly within muscle but selectively distributes into MIF. Simulations using a hybrid physiologically based pharmacokinetic model which describes uptake of drug only into the interstitial space showed good agreement between predicted and observed concentration data obtained from microdialysis sampling, supporting the findings that gallamine selectively distributes into MIF. These studies demonstrate microdialysis combined with conventional terminal tissue sampling provides valuable information on intra‐tissue drug distribution. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 769–775, 2002