CLINICAL-SIGNIFICANCE OF SERUM TOTAL BILE-ACIDS AND INDOCYANINE GREENTEST FOR THE ESTIMATION OF PLASMA-FREE ETOPOSIDE RATIO IN ANICTERIC HEPATOCELLULAR-CARCINOMA PATIENTS

Etoposide, an oil anticancer agent, has shown problematic interpatient variability in absorption in the intestine as well as excretion in th e liver. Bone marrow suppression occurs easily in the case of increase d plasma free etoposide fraction. In this study, we investigated a pos sible method for the pharmacokinetic estimation of free plasma etoposi de using serum markers; such as, fasting serum total bile acid (TEA) a nd indocyanine green (ICG). The subjects for this study included nine patients with hepatocellular carcinoma complicated by anicteric liver cirrhosis (LC-HCC), five cancer patients (except HCC) without liver dy sfunction. Oral dosage of etoposide was 50 mg kg(-1) body weight day(- 1). Total etoposide was measured using ultrasensitive HPLC, and protei n-unbound etoposide was determined using the same HPLC method after ul trafiltration. In the LC-HCC group, maximum free etoposide level was d etected 4 h after administration in all patients. The free ratio after 4 h was 12.97% (mean). On the other hand, in cancer patients (except HCC) with normal liver function, almost all the patients (four of five ) had no free etoposide. We have developed a formula which estimates t he protein unbinding ratio 4 h after administration (%) (Ratio-4 h). U sing regression analysis, ICG, TEA, and platelet were found to be impo rtant factors, and the following formula was obtained using stepwise r egression analysis: Predicted value (Ratio-4 h) = 0.001 x TBA + 0.004 x ICG + 0.011(R-2 = 0.811, P < 0.001). In conclusion, it was demonstra ted that serum fasting TEA and ICG could be significant markers for th e evaluation of etoposide pharmacokinetics, especially the protein unb inding ratio. (C) 1997 Elsevier Science Ireland Ltd.