Drug concentrations in the lymph of the hindquarters of sheep were used to gain insight into drug disposition within the interstitial space. Lidocaine, procainamide and meperidine were each infused into the right atrium of adult merino ewes for 220 min. The time courses of drug concentrations in arterial and inferior vena caval (IVC, draining the hindquarters) blood and hindquarter lymph were determined. It was found that in unanesthetized sheep the mean (+/- S.D., n = 3) lidocaine, procainamide and meperidine concentrations in the hindquarter lymph, were 74 +/- 11, 107 +/- 25 and 94 +/- 17%, respectively, of the arterial and 92 +/- 15, 113 +/- 27 and 134 +/- 28%, respectively, of the IVC blood drug concentrations. Drug binding in lymph, determined by equilibrium dialysis, was not significantly higher than that in blood, except for lidocaine at an initial buffer concentration of 5 micrograms/ml. When the studies were repeated with different animals under halothane anesthesia, the lymph/arterial and lymph/IVC blood drug concentration ratios of the three drugs decreased to 66 +/- 9, 73 +/- 13 and 71 +/- 13% and 77 +/- 8, 88 +/- 19 and 85 +/- 10%, respectively. These values were all significantly lower than those in unanesthetized animals. The results suggest that drug protein binding in interstitial fluid and the status of the microcirculation are important determinants of drug distribution in the interstitial and intracellular spaces. The data also confirm the assumption made in pharmacokinetic studies based upon mass balance principles that the rate of drug removal from organs by lymph is negligible.