Hepatic transport of the synthetic somatostatin analog octreotide-SMS 201-995, (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Throl--and its novel derivative N-alpha-(alpha-D-glucosyl(1-4)-1-deoxy-D-fructosyl)-octreotide--SD Z CO-611, N-alpha-(alpha-D-glucosyl(1-4)-1-deoxy-D-fructosyl)-(D)Phe-Cys-Phe- (D)Trp-Lys-Thr-Cys-Throl--was studied. In rats SMS 201-995 showed a plasma elimination half-life of 1.2 +/- 0.2 hr; that of SDZ CO-611 was 1.9 +/- 0.3 hours. Within 120 min 66% of a mesenterically injected 4.4-nmol dose of SMS 201-995 was excreted in bile, but only 5.3% of SDZ CO-611 was excreted in bile. Biliary concentration of SMS 201-995 showed a maximum enrichment of 540-fold +/- 75-fold over peripheral blood concentration, indicating hepatic transport mechanisms different from simple diffusion. Comparison of plasma profiles of both peptides after mesenteric and femoral administration demonstrated the relative importance of hepatic extraction for SMS 201-995 but not for SDZ CO-611. The mode of extraction was studied by means of multiple-indicator dilution in isolated perfused rat liver, with inulin as nonpermeable marker. Ratio plots, ln([inulin]/[peptide]) vs. time, exhibited decreasing slopes for SMS 201-995, suggesting very rapid binding to hepatocyte membranes. The slope of the ratio plot of (inulin/SDZ CO-611) was almost zero even at low doses (down to 0.2 microgram), implying mainly extracellular distribution and nonhepatic elimination. Binding assays indicated the absence of somatostatin receptors in sinusoidal hepatocyte membranes. However, SMS 201-995 and SDZ CO-611 bound with high affinity to somatostatin receptors in rat cortical membranes. Multiple-indicator dilution experiments in presence of increasing cholyltaurine concentrations suggested an interaction of SMS 201-995 with sinusoidal bile salt transport. In isolated hepatocytes, uptake of SMS 201-995 was saturable and showed mutual inhibition with cholyltaurine. The results indicate that SMS 201-995 transport is different from receptor mediated endocytosis as known for peptide hormones and elimination pathways of SDZ CO-611 other than biliary excretion.