Extrahepatic metabolism of morphine occurs in humans. The pharmacokinetics of morphine was studied in six patients in whom a radiologic localization of an insulinoma was to be performed under general anesthesia. Sampling was done in the peripheral artery, the mesenteric vein in five of the six patients, the hepatic vein, and the peripheral vein, as well as in urine. Hepatic blood flow was estimated by an indocyanine green infusion technique at the end of the radiologic procedure. Morphine terminal half-life was 92 +/- 9 minutes, total body clearance was 1260 ml.min-1, and the hepatic extraction ratio was 0.65 +/- 0.11. No concentration gradient was observed between the artery and the superior mesenteric vein, showing that no gut wall metabolism of morphine occurred. The total body clearance exceeded the hepatic clearance by 38%. It was concluded that the extrahepatic extraintestinal clearance of morphine probably occurred through the kidney. 