Analysis of the Factors Influencing Drugs Pharmacokinetics in Disease State and Their Clinical Relevance


 Under the influence of the modern life styles, diseases show a tendency of becoming complex and chronic. As a result, long term medical intervention has also become inevitable. In the treatment of patients, the risk of therapeutic failure or poor control of the disease is present. This is because in addition to the drug side effects that will also be experienced by a healthy person who received similar drug treatment, the pathological state of a disease may evoke unexpected drug effects can be classified into two category, namely, a consequence of altered pharmacodynamics, i.e. change in target protein sensitivity; and a consequence of altered pharmacokinetics, i.e. change in absorption, distribution, metabolism, and excretion of the drug. Hence, needless to say that a thorough understanding of the drug pharmacokinetics under different disease states is extremely important.
In chronic renal failure patients, uremic toxins which are harmful metabolites, have been found to accumulate to a high degree in occurrence of the uremic plasma. In order to overcome the complication that inhibits the QOL of dialysis patients, to prevent the adverse effects of drugs in chronic renal failure patients, it is necessary to clarify the interaction mechanism between biogenic molecule and uremic toxins.
 Recently, we have reported that uremic toxins such as indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indoleacetate and hippurate play an important role in the inhibition of serum protein binding of drugs in chronic renal failure. In addition, we have shown in pharmacokinetic analysis using rats that, these uremic toxins are mainly eliminated from plasma via active tubular secretion of the kidney. Subsequently, rat organic anion transporter 1 (rOat1) and rOat3 have been shown to involve in their uptake on renal basolateral membrane of the proximal tubules using stable transfectants of rOat1, rOat3 and rat kidney slices. In addition, human OAT1 (hOAT1) and hOAT3 have also shown to involve in the renal uptake of uremic toxins. Recent findings suggest that uremic toxins promote the progression of renal failure by damaging tubular cells . Consequently, increased concentrations of uremic toxins in the renal tubules would exacerbate the deterioration of renal function in chronic renal failure, suggesting that OATs-mediated uptake of these toxins lead to further loss of nephrons.
 At present, we are attempting to predict the pharmacological alteration of drugs and expression mechanism of uremic syndrome from the pharmacokinetic properties of uremic toxins and pathophysiological condition of the patient. Research projects of the following topics are currently underway:

Analysis of the Factors Influencing Drugs Pharmacokinetics in Disease State and Their Clinical Relevance

 1. Molecular Mechanisms of the Tissue Distribution Properties of Uremic Toxins 

 2. Functional and Molecular Characterization of Drug Transporters in Disease State

 3. Clinical Therapeutic Strategy Utilizing the Drug-Drug Interaction Phenomena

 4. Stereoselectivity in the Pharmacodynamics



Shimoishi K, Anraku M, Kitamura K, Tasaki Y, Taguchi K, Hashimoto M, Fukunaga E, Maruyama T, Otagiri M.
An oral adsorbent, AST-120 protects against the progression of oxidative stress by reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure.Pharm Res. 24:1283-1289 (2007)

Kadowaki D, Anraku M, Tasaki Y, Kitamura K, Wakamatsu S, Tomita K, Gebicki JM, Maruyama T, Otagiri M. Related Articles, Links Effect of olmesartan on oxidative stress in hemodialysis patients. Hypertens Res. 30:395-402 (2007)

Deguchi T, Isozaki K, Yousuke K, Terasaki T, Otagiri M. Involvement of organic anion transporters in the efflux of uremic toxins across the blood-brain barrier. J Neurochem. 96:1051-1059 (2006).

Deguchi T, Takemoto M, Uehara N, Lindup WE, Suenaga A, Otagiri M. Renal clearance of endogenous hippurate correlates with expression levels of renal organic anion transporters in uremic rats. J. Pharmacol. Exp. Ther. 314:932-938 (2005).

Tahara H, Shono M, Kusuhara H, Kinoshita H, Fuse E, Takadate A, Otagiri M, Sugiyama Y. Molecular cloning and functional analyses of OAT1 and OAT3 from cynomolgus monkey kidney. Pharm Res. 22:647-660 (2005).

Deguchi T, Kouno Y, Terasaki T, Takadate A, Otagiri M. Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharm Res. 22:619-627 (2005).

Wakida N, Tuyen do G, Adachi M, Miyoshi T, Nonoguchi H, Oka T, Ueda O, Tazawa M, Kurihara S, Yoneta Y, Shimada H, Oda T, Kikuchi Y, Matsuo H, Hosoyamada M, Endou H, Otagiri M, Tomita K, Kitamura K. Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. J. Clin. Endocrinol. Metab. 90:2169-2174 (2005).

Takamura N, Maruyama T, Chosa E, Kawai K, Tsutsumi Y, Uryu Y, Yamasaki K, Deguchi T, Otagiri M. Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome. Drug Metab. Dispos. 33:596-602 (2005).

Ohtsuki S, Kikkawa T, Mori S, Hori S, Takanaga H, Otagiri M and Terasaki T. Mouse "reduced in osteosclerosis" transporter (Roct) functions as an organic anion transporter 3 (mOAT3) and is localized at abluminal membrane of blood-brain barrier. J. Pharmacol. Exp. Ther. 309:1273-1281(2004).

Deguchi T, Kusuhara H, Takadate A, Endou H, Otagiri M and Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int. 65:162-174 (2004).

Deguchi T, Nakamura M, Tsutsumi Y, Suenaga A and Otagiri M. Pharmacokinetics and tissue distribution of uraemic indoxyl sulphate in rats. Biopharm. Drug Dispos. 24:345-355 (2003).

Imai T, Yoshigae Y, Hosokawa M, Chiba K and Otagiri M. Evidence for the involvement of a pulmonary first-pass effect via carboxylesterase in the disposition of a propranolol ester derivative after intravenous administration. J. Pharmacol. Exp. Ther. 307:1234-1242 (2003).

Imai T, Nomura T and Otagiri M. Probenecid-induced changes in the clearance of pranoprofen enantiomers. Chirality 15:318-323 (2003).

Imai T, Nomura T, Aso M and Otagiri M. Enantiospecific disposition of pranoprofen in beagle dogs and rats. Chirality 15:312-317 (2003).

Tsutsumi Y, Deguchi T, Takano M, Takadate A, Lindup WE and Otagiri M. Renal disposition of a furan dicarboxylic acid and other uremic toxins in the rat. J. Pharmacol. Exp. Ther. 303:880-887 (2002).

Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M and Terasaki T. Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J. Neurochem. 83:57-66 (2002).

Imamura H, Komori T, Ismail A, Suenaga A and Otagiri M. Stereoselective protein binding of alprenolol in the renal diseased state. Chirality 14:599-603 (2002).

Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S and Terasaki T. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int. 61:1760-1768 (2002).

Sakai T, Yamasaki K, Sako T, Kragh-Hansen U, Suenaga A and Otagiri M. Interaction mechanism between indoxyl sulfate, a typical uremic toxin bound to site II, and ligands bound to site I of human serum albumin. Pharm. Res. 18:520-524 (2001).

Tsutsumi Y, Maruyama T, Takadate A, Shimada H and Otagiri M. Decreased bilirubin-binding capacity in uremic serum caused by an accumulation of furan dicarboxylic acid. Nephron 85:60-64 (2000).