CHROMOSOME-ABERRATIONS AND PHARMACOKINETICS IN PATIENTS RECEIVING TAUROMUSTINE AS EITHER A SINGLE OR A REPEATED DOSE

Tauromustine (TCNU) is an exploratory drug that has demonstrated activ ity in various solid tumors. We examined chromosome aberrations and pl asma levels of the drug in two groups of patients receiving either a s ingle dose of 130 mg/m(2) or 40 mg/m(2) on 3 consecutive days. Peak pl asma concentrations (mean +/-SD) were obtained at a similar time after both treatments, i.e., at 38 +/- 25, 32 +/- 24, 28 +/- 14, and 40 +/- 26 min after administration of 130 mg/m(2) on day 1 and after that of 40 mg/m(2) on days 1, 2, and 3, respectively. In addition, the cumula tive area under the curve (AUC value) determined after administration of 40 mg/m(2) x 3 was similar to that noted after treatment with a sin gle dose of 130 mg/m(2), i.e., 180 and 179 mu g min ml(-1), respective ly. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40 mg/m(2) producing 5.5% CAs and 130 mg/m(2) yielding 20 .9% CAs at 24 h after treatment. In addition, although the drug concen tration declined to a level under the detection limit between the dail y treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180 +/- 62.8 and 179 /- 115 mu g min ml(-1), respectively).