Phase I trials of oral camptothecins, including camptothecin (CPT) and irinotecan (CPT-11), have reported substantial interpatient variability in systemic exposure, which could result in suboptimal antitumor activity in some patients or enhanced risk for toxicity in others. This investigation evaluates the contribution of intestinal absorption and first-pass metabolism in the disposition of oral CPT and CPT-11, respectively. The transport of CPT in Caco-2 cell lines (validated model of intestinal drug transport) was concentration dependent and saturable (Vmax: 34 x 10(-5) cm/sec and Km: 20 microM), and was temperature dependent with an activation energy (Ea) of 11.7 kcal/mole. Cumulatively, this data was indicative of carrier-mediated intestinal transport. In addition, a reduction of transport in the presence of sodium azide plus deoxyglucose suggested ATP dependence. Thus, variable expression and availability of intestinal transporters could contribute to the observed wide variability in the exposure to oral CPT. CPT-11 is hydrolyzed by the ubiquitous enzyme carboxyl esterase to active SN-38, and first-pass metabolism of oral CPT-11 would include both intestinal and hepatic hydrolysis. Incubation of CPT-11 with S9 fractions of human liver and intestinal tissues resulted in variable rates of formation of SN-38. The mean (+/- SD) specific activities (pmoles/min/mg) were: liver (8.57 +/- 10.4, n = 8), duodenum (5.06 +/- 3.7, n = 4), jejunum (6.44 +/- 2.8, n = 5), ileum (4.81 +/- 2.4, n = 5), colon (1.93 +/- 1.5, n = 6), and rectum (0.82, n = 1). Interestingly, there was a decrease in SN-38 formation by tumor tissue compared to matched normal liver and colon tissues. Therefore variable first-pass metabolism could contribute to the substantial differences in the systemic exposures to CPT-11 and SN-38 in patients receiving oral CPT-11.