Effects of water deprivation on the pharmacokinetics of theophylline and one of its metabolites, 1,3‐dimethyluric acid, after intravenous and oral administration of aminophylline to rats

Abstract

It has been reported that the expressions of hepatic microsomal cytochrome P450 (CYP) 1A1/2, 2B1/2 and 3A1/2 were not changed in rats with water deprivation for 72 h (rat model of dehydration) compared with the controls. It has been also reported that 1,3-dimethyluric acid (1,3-DMU) was formed from theophylline via CYP1A1/2 in rats. Hence, it could be expected that the formation of 1,3-DMU could be comparable between the two groups of rats. As expected, after both intravenous and oral administration of theophylline at a dose of 5 mg/kg to the rat model of dehydration, the AUC of 1,3-DMU was comparable to the controls. After both intravenous and oral administration of theophylline to the rat model of dehydration, the Cl(r) of both theophylline and 1,3-DMU was significantly slower than the controls. This could be due to significantly smaller urinary excretions of both theophylline and 1,3-DMU since the AUC of both theophylline and 1,3-DMU were comparable between the two groups of rats. The smaller urinary excretion of both theophylline and 1,3-DMU could be due to urine flow rate-dependent timed-interval renal clearance of both theophylline and 1,3-DMU in rats.

Nanosized rods agglomerates as a new approach for formulation of a dry powder inhaler

“…6,7 However, there is a t endency to reduce its use due to its complicated pharmacokinetic characteristics. [8][9][10][11][12][13][14][15] It has a very narrow therapeutic window so that the range between the therapeutic dose and the toxic dose is quite narrow. 11,14,16,17 Theophylline is a poorly water-soluble drug.…”

Effects of water deprivation on drug pharmacokinetics: Correlation between drug metabolism and hepatic CYP isozymes

“…Thus, changes in CYP isozymes would have the most profound influence on drug targets with low or intermediate hepatic extraction ratio. We Significantly greater AUC of 6-hydroxychlorzoxazone in rats 2 Theophylline CYP1A1/2 (less via 3A1/2) to form 1,3-DMU Comparable AUC of 1,3-DMU in rats (Choi et al, 2007a) 3 Ipriflavone CYP1A1/2 and 2C11 Comparable Cl nr of ipriflavone in rats (Chung and Lee, 2008) 4 DA-8159 CYP3A1/2 Comparable Cl nr of DA-8159 in rats 5 Adriamycin CYP2B1/2 and 3A1/2 to form M3 and M4 from adriamycin and adriamycinol, respectively…”

“…Dehydration does not change protein expression of CYP1A2 and 3A1/2 (Kim et al, 2001a), and should therefore not influence 1,3-DMU formation. In fact, 72-h dehydration did not influence the AUC of 1,3-DMU after 5-mg/kg theophylline (intravenously) in male SD rats (Choi et al, 2007a), due to comparable in vitro Cl int values for the formation of 1,3-DMU in the two groups of rats (Choi et al, 2007a).…”

Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism

“…[35] In conclusion, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2 in rats. This result could help to explain the possible pharmacokinetic changes of furosemide in rat models of acute renal failure induced by uranyl nitrate, [40] diabetes mellitus induced by streptozotocin or alloxan, [41] protein/calorie malnutrition, [42] inflammation induced by Escherichia coli lipopolysaccharide [43] or Klebsiella pneumoniae endotoxin, [44] dehydration, [45] and mutant Nagase analbuminaemic rats [46] in which the protein expression and/or mRNA levels of CYP2C11, 2E1, 3A1…”