Research Title |
Department of Pharmaceutics, School of Pharmaceutical Sciences, Nagasaki University (1992 to date)
Liver plays an important role in drug disposition in the body, so that there is an increasing interest in improving treatment of liver diseases. It is desired that the administered drug distributes largely into the target site in the liver, as proposed to treat liver diseases e.g. localized tumor. Normal routes of drug administration by intravenous and oral administration route have difficulty in achieving a local site of action in the liver by inadequate delivery into liver as well as toxicity in other organs. Although the direct way of drug application to the liver surface should yield local drug distribution for drug delivery to the target site in liver, the drug absorption from the liver surface has not been reported in literature.
We have analyzed pharmacokinetically the absorption of organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in-vivo employing a cylindrical glass cell. The main purpose of this research is to obtain the information concerning the absorption mechanism from liver surface membrane, and to attain the effective drug targeting to the liver. Furthermore, we are examining the changes in absorption characteristics in the deseased state (CCl4- or D-galactosamine-treated rat) and the differences in the drug absorption from the peritoneal cavity with the injection site, for clinical application.
University of Southern California, School of Pharmacy, Prof. Vincent H.L. Lee, Department of Pharmaceutical Sciences
Dipeptide transporters PepT1 and PepT2 have been attracting interest because of their role in the absorption of several important drugs including beta-lactam antibiotics, ACE inhibitors, renin inhibitors, anti-tumor agent bestatin, and so on. To date, there has been a lot of work on the biochemical characteristics of PepT1 and PepT2 especially in intestine and kidney.
Generally, these points below need to be clarified.
Recently, dipeptide transporters have been found to be involved in the transport of dipeptide drugs across conjunctival epithelial cells. The efficiency with which these drugs are absorbed in the conjunctiva after topical administration in the eye is an important determinant of availability to the back of the eye (ciliary body and perhaps retina). The previous results suggested the existence of another isoform in conjunctival epithelial cells. The first goal is to elucidate the biochemical characteristics of putative PepTx isoform.
Department of Pharmaceutics, School of Pharmaceutical Sciences, Nagasaki University (1991 to 1994)
The significance of the intestinal microorganisms to pharmacokinetics and pharmacology has been emphasized with respect to their ability to metabolize drugs and foreign compounds. The hydrolysis of glycine conjugates by intestinal microorganisms is well documented in various species. In the previous reports, we demonstrated that glycine conjugate of salicylic acid (salicyluric acid) was metabolized to salicylic acid by intestinal microorganisms existing mainly in cecum and colon in rabbits, rats and dogs. The elucidation of the effect of amino acid moiety on the fate of salicylic acid is considered to offer a promising approach to developing an effective prodrug of salicylic acid.
Thus, we prepared salicylic acid (SA)-alanine, SA-glutamic acid, SA-methionine, SA-tyrosine and SA-glycylglycine conjugate as prodrugs having various physicochemical properties, and we analyzed the metabolism of SA prodrugs in the intestinal microorganisms, by developing a detailed pharmacokinetic model, and also by a model-independent approach.
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University (1988 to 1991)
Recently, various macromolecular drug carrier systems have been developed in order to control the in vivo behavior of drugs. However, their applications were often limited by their hepatic accumulation and degradation. Nevertheless, only little systematic information about the disposition properties of the carrier macromolecules are available.
In the series of investigation, the physicochemical, pharmacokinetic and pharmacological characteristics of polymeric prodrugs of mitomycin C(MMC), MMC-dextran conjugates having cationic (MMC-Dcat) and anionic (MMC-Dan) charges have been examined. The in vivo disposition study of MMC-Dcat in rats and mice demonstrated its remarkable accumulation in the liver, while MMC-Dan showed slow plasma clearance and slight accumulation in the liver. Negative charges of glycocalyx are randomly scattered all over the cell surface membrane including hepatocytes. Similar phenomenon should be generally observed in other polycationic macromolecules. It is of interest to examine the interaction of cationic macromolecules with the liver and explore the general feature in the in vivo fate of them. I investigated the behavior of model macromolecules with almost the same molecular weight but different electric charges in the perfused rat liver and the isolated hepatocytes.
Asialoglycoprotein receptor-mediated drug targeting to the liver has attracted great interest as a potential method to deliver drugs and macromolecules preferentially to specific cells in the liver. Natural desialylated glycoproteins such as asialoorosomucoid and asialofetuin have been employed for this purpose. Synthetic glycosylated protein (neoglycoprotein) has been utilized as an effective tool in elucidation of the characteristics of endocytosis via carbohydrate-recognition in the cell. Neoglycoproteins have several advantages over natural desialylated glycoproteins in mass and uniform production, control of the number and structure of sugar residues, and probable reduction of antigenicity. Neoglycoproteins have been studied as a prototype of receptor-mediated endocytosis.
I selected lactosaminated bovine serum albumin (Lac-BSA) as a model neoglycoprotein for examining the effect of chemical modification on systemic and hepatic disposition of proteins. Lac-BSA's binding to the cell surface and its subsequent internalization were investigated at the whole body, organ, and cellular levels. Finally, the hepatic disposition characteristics of Lac-BSA are compared with those of cationized protein with regard to the binding to the cell surface and internalization based on physiological pharmacokinetics.
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University (1986 to 1988)
The hepatobiliary transport system plays an important role in drug disposition in the body. Many investigators have attempted to quantify the individual transfer processes of drug from the blood to the bile. However, the individual transport processes are usually not evaluated by means of a single experimental system. Kakutani et al has developed an experimental system in which statistical moment analysis was adopted for a local organ perfusion experiment. An advantage of this approach is the ability to quantitatively assess drug disposition by dividing it into distribution and elimination aspects. Therefore, this theory should be useful to characterize the hepatobiliary transport and metabolism mechanism of drugs.
I carried out single-pass rat liver perfusion experiments to investigate the hepatobiliary transport system of phenol red showing the typical characteristics of organic anions including carrier-mediated transport in sinusoidal and/or bile-canalicular membranes of hepatocytes, protein binding in cytosol and conjugative metabolism. Phenol red was momentarily injected from the portal side to the perfused liver and its outflow dilution and biliary excretion were analyzed by statistical moment theory.
Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University (1985 to 1986)
Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University (1985 to 1986)