PROLONGED LIDOCAINE METABOLIZING ACTIVITY OF PRIMARY HEPATOCYTES WITHSPHEROID CULTURE USING POLYURETHANE FOAM AS A CULTURE SUBSTRATUM

Primary rat hepatocytes formed spheroids in the pores of polyurethane foam (PUF) used as a culture substratum. The hepatocytes in monolayer and spheroid stationary culture converted lidocaine to monoethylglycin exylidide (MEGX) which was N-deethylation of lidocaine. The metabolic activity of the hepatocytes/spheroid stationary culture system was 1.5 similar to 2.0-fold higher than that of monolayer culture for 10 days . The activity of albumin production and cell survival of hepatocytes in monolayer and spheroid cultures decrease due to lidocaine treatment dependend on the lidocaine concentration, but the activity and cell s urvival in PUF/spheroid stationary culture were maintained at a higher level than that in monolayer culture under the lidocaine treatment. W e developed a device for an in vitro liver model, drug metabolism simu lator (DMS), using a PUP/spheroid packed-bed module including 4.00 +/- 0.68 x 10(7) hepatocytes and analyzed pharmacokinetics of lidocaine i n a one-compartment model. Lidocaine clearance and extraction ratio of hepatocytes in the DMS corresponded to 1.354 +/- 0.318 ml/min/g-liver and 0.677 +/- 0.0159/g-liver, respectively (N = 4). These values were comparable with in vivo values, 1.930 ml/min g-liver and 0.965/g-live r reported by Nyberg (1977). Consequently, PUP/spheroid culture mainta ined high lidocaine metabolizing activity over a long term and seems t o provide a promising culture system as a drug metabolism simulator wh ich will be used for drug screening, cytotoxicity tests and prediction of pharmacokinetics.