PHARMACOKINETICS OF THE MULTIDRUG-RESISTANCE-CONVERTING DRUG DEXNIGULDIPINE AND ITS PYRIDINE METABOLITE M-1 IN THE PLASMA, TUMOR, AND RENALTISSUE OF TUMOR-BEARING WAG RIJ RATS/

The pharmacokinetics of oral dexniguldipine, a new multidrug-resistanc e-modifying agent under clinical evaluation, and its pyridine metaboli te M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij r ats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor und er the renal capsule. The pharmacokinetics were studied in four experi ments. After a single administration of dexniguldipine (30 mg/kg), tum ors and kidneys were collected after 5 (experiment 1), 34 (experiment 2), and 48 h (experiment 3). In the fourth experiment. dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. T he concentrations of dexniguldipine and M-1 could be determined in pla sma in most of the rats at up to 32 h after drug administration. The a rea under the curve (AUG) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of d exniguldipine were observed. The concentrations were highest in the mu ltiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of co rrelation (> 0.8) were established between the concentrations of dexni guldipine measured in plasma and tumor as well as renal tissue. Overal l, tumor-tissue concentrations of M-1 comprised one-third of the dexni guldipine concentrations measured.