Pharmacokinetics of intravenous methotrexate in mutant Nagase analbuminemic rats

It has been reported that the plasma (or serum) levels of albumin and globulins were lower and higher, respectively, than the serum levels in control rats. Hence, it could be expected that these changes could affect the renal clearance (Clr) of methotrexate in Nagase analbuminemic rats (NARs) due to changes in plasma protein binding values. Therefore, methotrexate at a dose of 100mg/kg was administered intravenously to control rats and NARs. The plasma protein binding of methotrexate in NARs was significantly greater (29.4% increase) than the controls, probably due to the considerable binding of the drug (34.2%) to 1.8% β‐plus 0.63% γ‐globulins. The Clr of methotrexate in NARs was significantly slower (36.1% decrease) than the controls, due to the significantly smaller Ae0–24h (25.8% decrease). The smaller Ae0–24h could be due to the significantly smaller free (unbound to plasma proteins) fractions of methotrexate in plasma (13.8% decrease) in NARs, since methotrexate was mainly excreted in the urine via glomerular filtration. However, the Clnr values were comparable between the control rats and NARs. This could be because methotrexate is not metabolized considerably via hepatic CYP isozymes based on control rats pretreated with SKF 525‐A (a nonspecific inhibitor of hepatic CYP isozymes in rats). Copyright © 2007 John Wiley & Sons, Ltd.

[1]  M. Lee,et al.  Pharmacokinetics of oltipraz in mutant Nagase analbuminemic rats. , 2006, Journal of pharmaceutical sciences.

[2]  Y. Choi,et al.  Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition , 1993, Journal of Pharmacokinetics and Biopharmaceutics.

[3]  W. L. Chiou,et al.  Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve , 1978, Journal of Pharmacokinetics and Biopharmaceutics.

[4]  M. Gibaldi,et al.  Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects , 1977, Journal of Pharmacokinetics and Biopharmaceutics.

[5]  C. McArdle,et al.  Score Based on Hypoalbuminemia and Elevated C-Reactive Protein Predicts Survival in Patients With Advanced Gastrointestinal Cancer , 2004, Nutrition and cancer.

[6]  E. J. Kim,et al.  Pharmacokinetics and pharmacodynamics of intravenous azosemide in mutant Nagase analbuminemic rats. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[7]  E. J. Kim,et al.  Pharmacokinetics of intravenous theophylline in mutant Nagase analbuminemic rats. , 2003, Life sciences.

[8]  E. J. Kim,et al.  Pharmacokinetics and pharmacodynamics of intravenous trasemide in mutant nagase aalbuminemic rats , 2003 .

[9]  C. McArdle,et al.  Albumin Concentrations Are Primarily Determined by the Body Cell Mass and the Systemic Inflammatory Response in Cancer Patients With Weight Loss , 2001, Nutrition and cancer.

[10]  J. Kwon,et al.  Factors influencing the protein binding of a new phosphodiesterase V inhibitor, DA-8159, using an equilibrium dialysis technique. , 2000, Biopharmaceutics & drug disposition.

[11]  H. Wada,et al.  Pharmacokinetics of cisplatin in analbuminemic rats , 1999, Biopharmaceutics & drug disposition.

[12]  J. Chládek,et al.  An in vitro study on methotrexate hydroxylation in rat and human liver. , 1997, Physiological research.

[13]  Chunyan Zhu,et al.  Disposition of warfarin in analbuminemic rats , 1990 .

[14]  R. Bremnes,et al.  Dose-dependent pharmacokinetics of methotrexate and 7-hydroxymethotrexate in the rat in vivo. , 1989, Cancer research.

[15]  Y. Kato,et al.  Further observations on the disposition characteristics of salicylic acid in analbuminemic rats. , 1989, Biopharmaceutics & drug disposition.

[16]  Y. Morino,et al.  Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. , 1987, Kidney international.

[17]  B. Bistrian.  Some practical and theoretic concepts in the nutritional assessment of the cancer patient , 1986, Cancer.

[18]  Y. Morino,et al.  Hepato-renal transport of phenolsulfonphthalein in analbuminemic rats: albumin is essential for hepatic compensatory elimination of a nephrophilic ligand in animals with renal dysfunction. , 1986, Journal of biochemistry.

[19]  Y. Morino,et al.  Role of plasma albumin in renal elimination of a mercapturic acid. Analyses in normal and mutant analbuminemic rats. , 1985, European journal of biochemistry.

[20]  Y. Morino,et al.  Renal secretion of phenolsulfonphthalein: analysis of its vectorial transport in normal and mutant analbuminemic rats. , 1985, The Journal of laboratory and clinical medicine.

[21]  W. L. Chiou,et al.  Sensitive and rapid high-performance liquid chromatographic method for the simultaneous determination of methotrexate and its metabolites in plasma, saliva and urine. , 1981, Journal of chromatography.

[22]  J. Paxton,et al.  Protein binding of methotrexate in sera from normal human beings: effect of drug concentration, pH, temperature, and storage. , 1981, Journal of pharmacological methods.

[23]  S. Nagase,et al.  Albumin-deficient rat mutant: an animal model for analbuminemia. , 1980, Jikken dobutsu. Experimental animals.

[24]  W. L. Chiou.  New calculation method of mean total body clearance of drugs and its application to dosage regimens. , 1980, Journal of pharmaceutical sciences.

[25]  S. Nagase,et al.  Albumin-deficient rat mutant. , 1979, Science.

[26]  W. L. Chiou.  New calculation method for mean apparent drug volume of distribution and application to rational dosage regimens. , 1979, Journal of pharmaceutical sciences.

[27]  Howard M. Rawnsley,et al.  Clinical biochemical and hematological reference values in normal experimental animals , 1977 .