BIDIRECTIONAL TRANSPORT OF IMINODIACETIC ORGANIC ANION ANALOGS BETWEEN PLASMA AND HEPATOCYTE

The kinetics of organic anions are well described and back-diffusion f rom hepatocyte to plasma is accepted. Although iminodiacetic (IDA) ana logues, as organic anions, should also show bidirectional transport be tween hepatocyte and plasma, this has not been directly demonstrated h eretofore. The aim of this study was to directly demonstrate back-diff usion and to quantify it in terms of its fractional rate constant. Kin etics of diethyl IDA were studied in three anaesthetised dogs In which femoral arterial and hepatic venous samples were obtained after injec tion of tracer into (a) a peripheral vein or (b) hepatic artery or por tal vein. Arterial time-concentration curves were also compared betwee n peripheral venous and either hepatic arterial or portal venous injec tions. Time-activity curves were recorded from regions of interest ove r the cardiac blood pool and peripheral hepatic parenchyma in 30 patie nts undergoing routine IDA hepatobiliary imaging with diethyl IDA or m ebrofenin and fractional rate constants of clearance of IDA from the h epatocyte compared between compartmental and deconvolution analyses, A fter peripheral injection in dogs. there was an early arteriovenous co ncentration gradient across the liver indicating an hepatocyte extract ion fraction in the three animals of 0.9, 0.8 and 0,6. The net extract ion fraction decreased exponentially over 40 min. Time-concentration c urves from hepatic vein and femoral artery were virtually superimposed following intrahepatic injections. Peripheral arterial curves, howeve r, had different shapes according to whether injections were intrahepa tic or peripheral, and were consistent with significant back-diffusion . In clinical studies, the blood disappearance curves were fitted as t he sum of two exponentials and the liver curves as the difference of t wo exponentials (with rate constants denoted alpha(1)(h) and alpha(2)( h)), Based on compartmental analysis of the blood curves, the sum of t he fractional rate constants of tracer movement from hepatocyte to bil e canaliculus (k(32)) and to plasma (k(12)) was similar to and correla ted with the rate constant, a, of the hepatocyte impulse response func tion (r=0,62, n=30, P<0.001). In contrast, alpha(1)(h) and alpha(2)(h) were respectively clearly greater and smaller than alpha, Moreover, n either of these hepatic rate constants correlated with alpha. Diffusio n of IDA from hepatocyte to blood is significant and even in the prese nce of normal liver function accounts for about 50% of IDA transport o ut of the hepatocyte, It should be taken into account in pharmacokinet ic studies based on either compartmental or deconvolution analysis.