Isoniazid plasma and lymph kinetics after intravenous injection in dogs

Isoniazid pharmacokinetics after bolus intravenous injection in dogs has been studied using concentration measurements in plasma and in the lymph collected as the outflow of the thoracic duct. Simple graphical analysis as well as fitting of the data indicates that the plasma concentration exhibits biexponential decrease whereas three exponential components are detected in lymphatic kinetics. The discrepancy in the number of exponentials cannot be accounted for by a catenary three-compartment model. Another model, which is compatible with the anatomo-physiological characteristics of the lymphatic circulation is proposed. To account for transfer delays between the plasma-lymph exchange areas and the site of measurement, we assume that the drug concentration in the lymph collected at the extremity of the thoracic duct is the convolution of the interstitial lymphatic concentration with an exponential distribution of transit times. Assuming, furthermore, that a rapid equilibrium between plasma and interstitial lymph is established and that variations in the lymphatic flow are negligible, this model provides an adequate description of isoniazid plasma and lymph kinetics as can be judged from: 1. the satisfactory adjustment of model predicted values to the concentration measurements after global nonlinear least-squares fitting of plasmatic and lymphatic data; 2. the agreement of the estimated isoniazid pharmacokinetic parameters with values reported in literature. This agreement suggests that lymphatic concentrations at the exit of the thoracic duct give an indirect and distorted picture of interstitial fluid isoniazid levels whose kinetics, in fact, closely follows that existing in plasma.