Reduced Liver Uptake of Arterially Infused Melphalan during Retrograde Rat Liver Perfusion with Unaffected Liver Tumor Uptake JOOST ROTHBARTH, ROLF W. SPARIDANS, JOS H. BEIJNEN, LEO J. SCHULTZE KOOL, HEIN PUTTER, CORNELIS J. H. VAN DE VELDE, and GERARD J. MULDER Departments of Surgery (J.R., C.J.H.V.) and Medical Statistics (H.P.), Leiden University Medical Center, and Division of Toxicology (G.J.M.), Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; Faculty of Pharmacy (R.W.S, J.H.B.), Utrecht University, Utrecht, The Netherlands; and Department of Radiology (L.J.S.K.), Leiden University Medical Center/Netherlands Cancer Institute, Amsterdam, The Netherlands Received April 23, 2002; accepted July 22, 2002 ABSTRACT Isolated hepatic perfusion (IHP) with melphalan is used for patients with nonresectable metastases confined to the liver. To improve the efficacy of IHP and to reduce the toxicity to the liver, reversion (retrograde perfusion) of the bloodstream through the liver in a rat model was studied. For liver tumor induction male WAG/Rij rats were inoculated with CC531 cells, a colorectal tumor cell line. After 11 to 12 days the tumor- bearing rat livers were perfused by single-pass perfusion through either the portal (orthograde) or caval vein (retrograde) for different time periods. During perfusion melphalan (160 M) was infused in the hepatic artery. Melphalan concentrations were measured by high-performance liquid chromatography. A rapid extraction of melphalan by the liver occurred in the first 5 min, reaching steady state after 10 to 20 min for both perfusion directions. The melphalan concentration of the outflow perfus- ate was significantly higher in the retrograde perfusion com- pared with the orthograde perfusion. The melphalan content of the tumor tissue was unaffected by perfusion direction at any time point. To the contrary, the melphalan uptake in liver tissue was strongly influenced: the melphalan content after 40-min ret- rograde perfusion was 12% of that after orthograde perfusion. The average tumor/liver concentration ratio was 6 for orthograde per- fusion and 30 for retrograde perfusion. In conclusion, retrograde IHP with continuous melphalan infusion in the hepatic artery pro- vides a high tumor uptake of melphalan with potentially reduced liver toxicity compared with orthograde IHP. Isolated hepatic perfusion (IHP) is a treatment for patients with nonresectable metastases confined to the liver, allowing local treatment with high-dose chemotherapy. Because of this high exposure, promising tumor responses and survival rates have been observed (Alexander et al., 1998; Vahrmeijer et al., 2000). However, the percentage of patients with com- plete remission is still very limited and toxicity remains a major complication. Therefore, new strategies for drug ad- ministration during IHP to improve the efficacy of IHP and to reduce the toxicity to the liver are still needed. Anatomical studies show that metastasizing tumor cells entering the liver via the portal vein develop into liver tu- mors, which are mainly vascularized by the hepatic artery (Sigurdson et al., 1987). Studies of the blood supply of liver tumors show that the hepatic artery provides up to 95% of their total blood flow (Wang et al., 1994); contrary to normal liver tissue, the portal vein plays a minor role in the blood supply of liver tumors (Taylor et al., 1978). The liver sinusoids are perfused with blood from both the portal vein and hepatic artery. Studies of the blood supply of the rat liver show that the hepatic arterioles terminate in the first one-third of the sinusoids (zone 1) via an indirect or direct pathway (Fig. 1) (Rappaport, 1980; Watanabe et al., 1994). As a result, the arterial blood reaches all zones of the sinusoid in orthograde perfusion. However, during retro- grade perfusion, i.e., using the portal vein for outflow instead of the caval vein, the arterial blood only reaches zone 1, the periportal parts (Pang et al., 1988). Thus, when IHP is per- formed in the retrograde way, whereas high-dose chemother- apy is only infused via the hepatic artery, the exposure of the whole liver to the cytostatic compound will be reduced, and so probably also liver toxicity. Therefore, retrograde perfusion potentially provides increased safety. As liver tumors obtain most of their blood supply from the hepatic artery, retrograde perfusion is not expected to affect the exposure of liver tu- mors to arterially administered cytostatic compounds. To explore the consequences of altered flow direction on the This study was supported by Grant 2000-2198 from the Dutch Cancer Society (to K.W.F.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.037895. ABBREVIATIONS: IHP, isolated hepatic perfusion; HPLC, high-performance liquid chromatography; d p , particle density. 0022-3565/02/3032-736 –740$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 303, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 37895/1021269 JPET 303:736–740, 2002 Printed in U.S.A. 736 at ASPET Journals on July 19, 2018 jpet.aspetjournals.org Downloaded from