Pharmacokinetics of intravenous theophylline in mutant Nagase analbuminemic rats

Kim, Eun Jung; Suh, Ok Kyung; Lee, Myung Gull

doi:10.1016/s0024-3205(02)02373-1

Cited by 15 publications

(20 citation statements)

References 27 publications

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“…Kim et al [6] reported that in NARs, the expression and the mRNA level of the hepatic microsomal cytochrome P450 (CYP) 1A2 increased, but those of CYP2E1 and 3A1/2 did not change compared with the controls. In previous studies, the hepatic CYP isozyme changes were the prime reasons for the changes in the pharmacokinetics of some drugs, such as azosemide [6], theophylline [8] and oltipraz [11] in NARs. Therefore, it could be expected that changes in the plasma concentrations of albumin and globulins [9] and hepatic CYP isozyme changes [6] would affect the pharmacokinetics of methotrexate in NARs, if plasma protein binding of methotrexate is changed and methotrexate is metabolized via CYP1A2 in NARs.…”

Section: Introductionmentioning

confidence: 97%

“…This phenomenon, elevated Creactive protein concentrations and hypoalbuminemia, occurs in cancer patients including those with breast cancer [16]. Although pharmacokinetic changes of drugs in NARs have been reported [1][2][3][4][5][6][7][8]11,[17][18][19], studies on methotrexate in NARs have not been reported yet. Hence, methotrexate was chosen in this study using NARs as an animal model.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of intravenous methotrexate in mutant Nagase analbuminemic rats

Choi

Bae

et al. 2007

Biopharm & Drug Disp

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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 (Cl(r)) of methotrexate in Nagase analbuminemic rats (NARs) due to changes in plasma protein binding values. Therefore, methotrexate at a dose of 100 mg/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% beta-plus 0.63% gamma-globulins. The Cl(r) of methotrexate in NARs was significantly slower (36.1% decrease) than the controls, due to the significantly smaller Ae(0-24h) (25.8% decrease). The smaller Ae(0-24h) 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 Cl(nr) 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).

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of intravenous methotrexate in mutant Nagase analbuminemic rats

Choi

Bae

et al. 2007

Biopharm & Drug Disp

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“…Many studies regarding the pharmacokinetic characteristics of various drugs in Nagase analbuminemic rats have been published (2,3,(7)(8)(9)18). …”

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confidence: 99%

Role of Plasma Proteins in Pharmacokinetics of Micafungin, an Antifungal Antibiotic, in Analbuminemic Rats

Abe

Ueyama

Kawasumi

et al. 2008

Antimicrob Agents Chemother

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There were no significant differences in the pharmacokinetics of micafungin and expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2) between analbuminemic and Sprague-Dawley rats. Micafungin bound strongly to high-density lipoprotein (HDL) and moderately to gamma globulin. These results suggest that HDL and gamma globulin contribute to the pharmacokinetics of micafungin.Micafungin is widely used for the treatment and prevention of various fungal infections. This antibiotic appears to be predominantly eliminated by hepatic cytochrome P450 (CYP)-mediated metabolism and partly excreted in unchanged form in the feces via hepatobiliary excretion, whereas urinary excretion is a minor excretion route (6,12,20). Moreover, it has also been reported that micafungin has no effect on the metabolism of various substrates for CYP isoforms such as CYP3A4, CYP1A2, and CYP2C9 (4,5,14,16). We have recently demonstrated that micafungin is excreted into bile mainly by multidrug resistance-associated protein 2 (ABCC2/Mrp2) and partly by ABCB1/P-glycoprotein, and its plasma protein binding level is very high (Ͼ99%) in Sprague-Dawley (SD) rats (1). The effect of plasma protein binding on the pharmacokinetics of micafungin, however, is not clear yet.Nagase analbuminemic rats, which have been established from SD rats, are characterized by a considerably low plasma albumin concentration and hyperlipidemia (13). Many studies regarding the pharmacokinetic characteristics of various drugs in Nagase analbuminemic rats have been published (2,3,(7)(8)(9)18).The present study aims to clarify the role of plasma proteins such as albumin, high-density lipoprotein (HDL), and gamma globulin in the pharmacokinetics of micafungin in analbuminemic rats.Standard solutions of micafungin and FR195743 (an internal standard) were kindly supplied by Astellas Pharma Inc. (Tokyo, Japan). Micafungin for injection was purchased commercially. Human serum albumin (HSA) was obtained from Sigma Chemicals (St. Louis, MO). Human HDL and gamma globulin were purchased from Wako Chemicals (Tokyo, Japan). C219 mouse monoclonal antibody to P-glycoprotein (Dako, Glostrup, Denmark), human monoclonal antibody against Mrp2 (Alexis Biochemicals, San Diego, CA), mouse monoclonal antibody to ␤-actin (Sigma), and horseradish peroxidase-conjugated anti-mouse immunoglobulin G (GE Healthcare UK Ltd., Buckinghamshire, United Kingdom) were used for Western blotting. All other reagents were obtained commercially and were of the highest purity available. Micafungin, HSA, gamma globulin, and HDL were dissolved in saline.Male SD rats (8 weeks old; body weight, 270 to 295 g) and male Nagase analbuminemic rats (body weight, 225 to 250 g) of the same age as the SD rats were obtained from Japan SLC Inc. (Hamamatsu, Japan). The rats were housed under controlled environmental conditions (temperature of 23 Ϯ 1°C and humidity of 55% Ϯ 5%) with a commercial diet and water freely available. All animal experiments were carried out in accordance with the guidelines of Aichi Med...

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“…More than 91.8 and 94.5% of the spiked amounts of theophylline were recovered from various buffer solutions and rats' gastric juices, respectively, using a reported method (Yu et al, 2003). Kim et al (2003) reported that the contribution of the biliary excretion of unchanged theophylline to the CL NR of theophylline is almost negligible. Thus, the CL NR of theophylline listed in Table 1 could represent the metabolic clearance of theophylline.…”

Section: Resultsmentioning

confidence: 99%

Time-Dependent Effects of Klebsiella Pneumoniae Endotoxin (KPLPS) on the Pharmacokinetics of Theophylline in Rats: Return of the Parameters in 96-Hour KPLPS Rats to the Control Levels

Yang

Jung²,

Lee³

et al. 2008

Drug Metab Dispos

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ABSTRACT:It has been reported that theophylline is primarily metabolized via hepatic CYP1A1/2, 2B1/2, and 3A1/2, and 1,3-dimethyluric acid (1,3-DMU) is primarily formed via CYP1A1/2 in rats. Compared with control rats, the expression of CYP1A subfamily, 2B1/2, and 3A subfamily significantly decreased 24 h (24-h KPLPS rats) after intravenous administration of lipopolysaccharide derived from Klebsiella pneumoniae (KPLPS) to rats but returned to that in control rats after 96 h (96-h KPLPS rats). After intravenous or oral administration of theophylline to 24-h KPLPS rats, the values for the total area under the plasma concentration-time curve from time zero to time infinity of theophylline and 1,3-DMU became significantly greater (46.5 and 34.0% increase after intravenous and oral administration, respectively) and smaller (36.3 and 21.6% decrease, respectively), respectively. Because theophylline is a low hepatic extraction ratio drug in rats, the above results could have been due to significantly slower CL int for the disappearance of theophylline and for the formation of 1,3-DMU (37.1 and 60.6% decrease, respectively). However, in 96-h KPLPS rats, the pharmacokinetic parameters of theophylline and 1,3-DMU returned fully or partially to those in control rats. These findings indicate the existence of time-dependent effects of KPLPS on the pharmacokinetics of theophylline and 1,3-DMU in rats.Theophylline, a bronchodilator, has widely been used for the management of acute bronchospasm associated with asthma or chronic obstructive pulmonary disease. It is metabolized to 1-methylxanthine (MX), 3-MX, and 1,3-dimethyluric acid (1,3-DMU), and 1-MX is further metabolized to 1-methyluric acid via xanthine oxidase in rats (McManus et al., 1988). Recently, Yang et al. (2008) reported that theophylline is primarily metabolized via hepatic microsomal cytochrome P450 (P450) 1A1/2, 2B1/2, and 3A1/2 (but not via CYP2C11, 2D6, and 2E1), and 1,3-DMU was primarily formed via CYP1A1/2 in male Sprague-Dawley rats.Lipopolysaccharide (LPS) is an active component in the outer membrane of Gram-negative bacteria. There have been several studies on changes in the expression of hepatic P450 isozymes in rats pretreated with LPS derived from Klebsiella pneumoniae (KPLPS) (Nadai et al., 1998;Ueyama et al., 2005). However, to our knowledge, no studies on changes in the expression of hepatic CYP1A subfamily, 2B1/2, and 3A subfamily in rats pretreated with KPLPS after 24 h (24-h KPLPS) and 96 h (96-h KPLPS) based on Western blot analysis have yet been reported. It has been reported that inflammation is triggered in rats by a small dose of LPS (Deng et al., 2006), bacterial infection is an important factor in bronchial asthma (Oehling, 1999), and Gram-negative bacterial infections are common in patients with chronic obstructive pulmonary disease combined with pneumonia (Yi et al., 2003). Thus, we examined theophylline in this study.The aim of this study was to investigate changes in pharmacokinetics of theophylline and 1,3-DMU after intravenous or o...

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Pharmacokinetics of intravenous theophylline in mutant Nagase analbuminemic rats

Cited by 15 publications

References 27 publications

Pharmacokinetics of intravenous methotrexate in mutant Nagase analbuminemic rats

Pharmacokinetics of intravenous methotrexate in mutant Nagase analbuminemic rats

Role of Plasma Proteins in Pharmacokinetics of Micafungin, an Antifungal Antibiotic, in Analbuminemic Rats

Time-Dependent Effects of Klebsiella Pneumoniae Endotoxin (KPLPS) on the Pharmacokinetics of Theophylline in Rats: Return of the Parameters in 96-Hour KPLPS Rats to the Control Levels

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