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Pharmacokinetics of Intravesical Mitomycin C in Superficial Bladder Cancer Patients¹

College of Pharmacy [J. T. D., J. L-S. A.] and Division of Urology [M. G. W., R. A. B., J. R. D.], The Ohio State University, Columbus, Ohio 43210

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 ± 34.8 µg/ml (mean ± SD) in the dosing solution to 64.6 ± 39.4 µg/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to >34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185–40,411 µg-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P < 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P < 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P < 0.001). At pH between 5 and 5.5, <30% of the dose was recovered. In vitro incubation of MMC in urine demonstrated a 44% decrease in MMC concentrations after 2 h at pH 5, as compared to <4% loss at pH 7. Therefore, degradation accounted for more than one half of the drug loss at low pH. In conclusion, these data indicate the large target site specificity of intravesical MMC, the variable but insignificant systemic exposure to MMC, and the large variability in target site exposure to MMC. The data further demonstrate the effect of residual urine volume, urine production, and drug removal by degradation and absorption during bladder exposure to MMC.

¹ Supported in part by a research grant, ROI CA-49816, and a Research Career Development Award to J. L-S. A. (K04 CA-01497) from the National Cancer Institute, NIH, DHHS. J. T. D. was supported in part by a fellowship from the American Foundation for Pharmaceutical Education.

² To whom requests for reprints should be addressed, at College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210.

Received 3/21/91. Accepted 7/18/91.

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