2007 Fiscal Year Final Research Report Summary
Mechanisms responsible for interindividual variability of bioavailability of therapeutic compounds in patients with acute renal failure and related homeostasis perturbation
| Project/Area Number |
18590141
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Medical pharmacy
|
|---|
| Research Institution | Okayama University |
|---|
Principal Investigator |
AIBA Tetsuya Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Ph.D.Associate Profrssor (00231754)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KUROSAKI Yuji Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Ph.D.S, Professor (90161786)
KAWASAKI Hiromu Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Ph.D.Professor (60125151)
KOMORI Yukiko Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, M.Sc.Research Instructor (80379734)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Keywords | Renal failure / Pharmacokinetics / Cephalexin / Tolhutamide / unidine / NKCCl / TRPVl / Pharmacodynamics |
|---|
| Research Abstract |
Mechanisms responsible for blood concentration of therapeutic compounds being considerably altered in acute renal failure were investigated. It was shown that protein unbound fraction of a representative compound quinidine is decreased in acute renal failure, whereas those of acid compounds, such as tolbutamide, has been known to be increased. The decreased unbound fraction of quinidine seems to be related to the fact that the hepatic production of alpha-1 acid glycoprotein (AGP) increases in acute renal failure, resulting in an increase in the plasma AGP concentration. In addition, we revealed that lithium disposition to cerebrospinal fluid (CSF) decreases when the kidney function is impaired, and that the choroid plexial expression of NKCC1 increases in acute renal failure. Therefore, it is plausible that the decreased lithium disposition to CSF is caused by an increased lithium efflux from CSF due to an increased NKCC1 expression in the choroid plexus. We also found that the transporter-mediated intestinal absorption of cephalexin is suppressed by stimulating a cation channel TRPV1 expressed on afferent neurons innervating gastro-intestinal tract. As afferent neurons seem to play an important role in regulating intestinal drug absorption and its alternation in acute renal failure, future study should be conducted to clarify this.
|
