Cholephilic characteristics of a new cytostatic complex of cisplatin with glycocholate (Bamet-R2)
Introduction
Since the use of bile acid carrier mechanisms to enhance the hepatic and small intestinal absorption of drugs was first proposed [1], several attempts in this direction have been made 2, 3, 4, among them the synthesis of Bamet-R2 [5]. The existence of specific bile acid carrier proteins in the plasma membranes of hepatocytes and ileocytes [6], which are not present in most cell types, makes these cells ideal targets for bile acid-labeled drugs. Bamet-R2 can be considered one of the many second-generation platinum-containing compounds that have been developed in an effort to obtain new cytostatic drugs having fewer toxic side effects than cisplatin but with comparable chemotherapeutic efficacy. What makes Bamet-R2 peculiar is the use of endogenous compounds with marked liver organotropism – i.e., bile acids – to direct a cisplatin-derived drug toward the hepatobiliary system. These derivatives are expected to be more efficiently taken up by the liver than their parent drug [7]. The strategy also endows certain of these derivatives with enhanced hepatobiliary excretion. Owing to the previously reported cytostatic activity [5]and liver organotropism [8]of Bamet-R2, one could speculate that this compound might be potentially useful in the chemotherapy of liver tumors. However, it has been reported that bile acids cannot be envisaged as useful shuttles for cytostatic drugs toward liver-derived tumors because of the absence in liver tumor cell lines of efficient bile acid uptake, which is a phenotypical characteristic of differentiated hepatocytes [9]. This seems to be true, but only in part. Thus, it has been reported that Na+-dependent bile acid uptake is to a certain extent lost in rat hepatoma cells 10, 11, 12, 13. However, some degree of Na+-independent uptake is still present in liver tumor cells 13, 14, thus accounting for an efficient bile acid uptake, although lower than that of hepatocytes 13, 15.
Because only anionic bile acids are efficiently taken up by the Na+-dependent bile acid transport system located at the sinusoidal membrane of the hepatocyte, Bamet-R2, which is a neutral compound, is not expected to be a good substrate for this carrier. Nevertheless, efficient Bamet-R2 liver uptake has been reported [8]and the possibility of this occurring via a Na+-independent bile acid transport system has been suggested. This means that the absence of Na+-dependent bile acid transport systems in liver tumor cells will probably not affect the ability of these cells to take up Bamet-R2 to any great extent.
A second possibility to be considered is the use of Bamet-R2 in regional chemotherapy. Using isolated perfused rat livers, Bamet-R2 has been shown to be rapidly taken up from the perfusate and secreted into bile. Thus, efficient biliary elimination is also expected to occur after Bamet-R2 leaves the tumoral area during intraarterial administration.
The existence of carrier systems for bile acids in the intestine (mainly in the ileum) account for an efficient re-uptake of molecules that have reached the gut with bile [6]. Reabsorbed bile acids return to the liver via the portal vein. Thus, only a minor fraction of the bile acid pool is lost every day in the feces, while the rest remains sequestered within the so-called enterohepatic circulation. Whether Bamet-R2 shares this behavior with natural bile acids is an interesting question involving two important pharmacological issues: the re-exposure to Bamet-R2 of tumors located in the enterohepatic circuit and the ability of the body to eliminate this drug. The aim of this work was therefore to investigate the existence of enterohepatic circulation of Bamet-R2 and the relevance of biliary versus urinary excretion of this complex by using two experimental models: (i) intraluminal perfusion of `in situ' ileum in anaesthetized rats bearing a biliary fistula that permitted bile sample collection and (ii) conscious rats to which a permanent intraarterial catheter had been implanted to carry out sequential blood sampling after drug administration. At the end of these experiments, serum ultrafiltrable platinum was determined. However, in the rest of the study total platinum was used because this is related to both toxicity and anti-tumor efficacy 16, 17, 18, 19. Moreover, the use of ultrafiltrable platinum, although preferred by some investigators [20], has been questioned by others [21]due to the ill-defined mixture of species included in this term and to the unreproducible values found by different laboratories for this parameter, since different techniques to prepare and filter the samples have been used.
Section snippets
Chemicals and animals
Cisplatin was purchased from Sigma Chemical Co. (St Louis, MO). Bamet-R2 (cis-diamminechlorocholylglycinateplatinum(II)) was synthesized and chemically characterized as previously reported [5]. All other chemicals were from Merck (Darmstad, Germany). Male Wistar rats (200 g, five animals for each experimental group) were from the Animal House at the University of Salamanca, Spain. They were fed with commercial rat pelleted food (Panlab, Madrid, Spain) and water ad libitum. Temperature (20°C)
Results
The serum total platinum concentrations vs. time curves generated from rats receiving Bamet-R2 or cisplatin via intravenous (i.v.) or intragastric (i.g.) administration are shown in Fig. 1. Both Bamet-R2 and cisplatin disappeared rapidly from serum during the first day after i.v. administration. The process was slower for Bamet-R2 than for cisplatin (Fig. 1, upper panel). The serum concentrations of Bamet-R2 remained significantly higher than those of cisplatin for 48 h. A second phase with
Discussion
Bamet-R2 has been previously reported to be efficiently taken up by the isolated rat liver and secreted into bile [8]. The present study shows that although the intestinal absorption of Bamet-R2 occurs to a markedly higher extent than that of cisplatin, it is only moderately efficient in comparison with that of endogenous major bile acids [6]. Therefore, after a single i.v. injection or i.g. administration Bamet-R2 does not remain sequestered within the enterohepatic circulation for long.
Acknowledgements
This study was supported in part by the Ministerio de Educacion y Ciencia (Grants SAF94-0693 and SAF96-0146) Spain. Part of this work has appeared in abstract form in the Hepatology (1996) 24:372A:982.
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