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Uptake of the Noncytotoxic Transport Probe Procainamide in the Chinese Hamster Ovary Model of Multidrug Resistance¹

K. V. Speeg, Jr.², Catherine deLeon and William L. McGuire

Department of Medicine, Divisions of Gastroenterology/Nutrition [K. V. S., C. D.] and Oncology [W. L. M.], The University of Texas Health Science Center at San Antonio and Audie Murphy VA Hospital, San Antonio, Texas 78284

Many of the cytotoxic substrates of the multdrug transporter are organic cations. Cimetidine, procainamide, and tetraethylammonium bromide were used in a Chinese hamster ovary model of multidrug resistance, to study handling of noncytotoxic cationic transport probes. Cimetidine and procainamide, but not tetraethylammonium, accumulated to a greater extent (5-fold) in the sensitive CHOAUXB1 (AB) cell line than in the resistant CH^RC5 (C5) cell line. Accumulation of both cimetidine and procainamide was significantly increased by verapamil in C5 but not AB. Procainamide accumulation in both AB and C5 was temperature dependent and occurred by passive diffusion. Diltiazem, nifedipine, rifampin, tamoxifen, rhodamine, and ethidium also increased procainamide accumulation in C5 but not AB. Azide in glucose-free medium increased procainamide accumulation in C5, and this was reversed when glucose, but not 3-O-methylglucose, was added. Procainamide efflux rates were similar in AB and C5 and not affected by verapamil or azide. The initial rate of procainamide uptake was higher in AB than in C5, and both verapamil and azide increased the initial rate of procainamide uptake in C5. Thus, differences in accumulation of the noncytotoxic transport probe procainamide in the colchicine-sensitive and colchicine-resistant components of the Chinese hamster ovary cell line mimic the accumulation of known cytotoxic substrates for the multidrug transporter, such as colchicine, vinblastine, and doxorubicin. The differential accumulation of procainamide is due to differences in rates of drug influx, rather than efflux. Since procainamide influx is passive and decreased accumulation in the resistant line appears to parallel M_r 170,000 glycoprotein presence and activity, we would speculate that decreased procainamide accumulation may be due to an indirect effect of the M_r 170,000 glycoprotein, such as its effect on intracellular pH.

¹ This work was supported by NIH Grant CA30195 and the Veterans Administration Research Service and was reported, in part, at the meeting of the American Federation for Clinical Research, May 1988 (34).

² To whom requests for reprints should be addressed, at Department of Medicine/Gastroenterology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284.

Deceased.

Received 10/25/91. Accepted 4/23/92.