Transport and Binding of Methotrexate In Vivo

Dedrick, Robert L.; Zaharko, Daniel S.; Lutz, Robert J.

doi:10.1002/jps.2600620603

Cited by 143 publications

(26 citation statements)

References 23 publications

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“…1979], These studies in animals [B ischojf et al. 1970Dedrick et al, 1973;Henderson et al, 1965;Paxton. 1979;Yang el al.. 1979] de scribed the M T X kinetics for observation pe riods of 2.3-48 h. and mostly did not deter mine the drug's concentration in organs.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Scheufler¹,

Zetler²,

Iven³

1981

Pharmacology

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After intravenous injection of 31 mg/kg methotrexate (MTX), its concentrations were determined in plasma, liver, kidney, bone marrow, stomach, duodenum, jejunum, colon and muscle up to 23 days, using an enzymatic assay. Plasma pharmacokinetics were described by a triexponential function, with a terminal half-life of 4.2 h. Up to 1.5 h after injection, the initial rapid decline of MTX concentrations in bone marrow, kidney, and liver roughly paralleled that in plasma. The terminal half-life of MTX in bone marrow was greatly prolonged (37 h), while MTX remained nearly constant in liver (0.57 µg/ml) and kidney (0.53 µg/ml) from 6 h to 23 days. In the intestines, luminal as well as tissue MTX concentrations were determined. The stomach showed a triexponential decay of tissue MTX and low luminal concentrations throughout. In the duodenum, the middle of jejunum, and the colon tissue MTX seemed to follow a bi- or triexponential function. However, high luminal concentrations due to MTX biliary excretion, when reaching a given intestinal portion, increased the MTX tissue concentration in this segment.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Scheufler¹,

Zetler²,

Iven³

1981

Pharmacology

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“…In this model, equation 8 was introduced to describe the hepatic intrinsic clearance (CL int, lv ). (8) The mean of the physiological data for each animal taken from the literature [14][15][16][17] was used for the blood flow rate (Q) and tissue volume (V d ) parameters of each organ in the model. The reported values of the blood-to-plasma concentration ratio (R b ) and the tissue-to-plasma concentration ratio of free drug (K p, f ) for tolbutamide were also used.…”

Section: Methodsmentioning

confidence: 99%

Application of the PKCYP-test to Predict the Amount of in Vivo CYP2C11 Using Tolbutamide as a Probe.

Matsunaga¹,

Nishijima²,

Hattori³

et al. 2001

Biological & Pharmaceutical Bulletin

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It is important to be able to predict the drug clearance rate for individual patients in order to select the most appropriate drug dosage regimens. Many attempts have been made to evaluate the drug metabolism capacity of individual patients by using specific probe drugs for cytochrome P450 (CYP) isozymes. 1,2) In addition, several other approaches have been used to predict in vivo drug metabolism, scaling of in vivo metabolic clearance from in vitro data obtained using human liver microsomes or a recombinant system of human CYP isozymes. 3,4) In our previous work, we described a new method for assessing drug metabolism capacity based on a pharmacokinetic estimation of the quantity of CYP in vivo (PKCYPtest). 5,6) In setting up the PKCYP-test, an apparent liver-toblood free concentration gradient in vivo (qg) was introduced. In rats with fluctuating CYP1A2 levels, the amount of CYP could be predicted by the PKCYP-test using the clearance of acetanilide, as a probe drug, mediated by CYP1A2. Moreover, caffeine clearance mediated by CYP1A2 could also be predicted by using the predicted amount of CYP1A2. Several CYP isozymes are involved in in vivo drug metabolism and it is important to determine how useful the PKCYPtest is in the case of other CYP isozymes.CYP2C11 is the most abundant isozyme in liver microsomes from untreated male rats. 7) Although CYP1A2 is inducible, CYP2C11 is a constitutive CYP isozyme.8) Therefore, it is of interest to examine the application of the PKCYP-test to CYP2C11. It is necessary to choose a probe drug and an animal model which has fluctuating CYP2C11 levels in order to examine the application of the PKCYP-test to CYP2C11. Tolbutamide is reported to undergo a single pathway of primary metabolism which is believed to be catalyzed by CYP2C11 in rats.8) Moreover, it is well known that carbon tetrachloride (CCl 4 ) can be used to induce acute liver damage in rats. It has also been reported that the amount of CYP2C11 is reduced in rats treated with CCl 4 . 9) In the present study, we examined the amount of CYP2C11 in rats treated with CCl 4 to see if this could be predicted by using tolbutamide as a probe.To date, a physiologically-based pharmacokinetic model has been used as a method for analyzing the pharmacokinetics of drugs in a number of disease states. For example, serum and tissue concentrations of a drug in the presence of drug-drug interactions have been predicted by this model. 10)One of the advantages of this model is that the effects of fluctuations in the pharmacokinetic or physiological parameters on drug disposition can be simulated. Therefore, we constructed a physiologically-based pharmacokinetic model which involved the PKCYP-test and evaluated the effects of qg and the amount of CYP used as an indicator of hepatic metabolism capacity on drug disposition. Previous reports have shown that the determination of drug metabolism capacity can be made by the pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blo...

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“…where the measured plasma protein unbound fraction (f u ) and blood/plasma concentration ratio (Rb) are 0.01 and 0.57, respectively, and the hepatic blood flow rate (Q) in rats is 14.8 ml/min/250-g of rat (Dedrick et al, 1973). The total body clearance (CL tot ) based on in vivo infusion data was calculated according to the following equation:…”

Section: Z-335mentioning

confidence: 99%

Carrier-Mediated Active Transport of a Novel Thromboxane A₂ Receptor Antagonist [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) into Rat Liver

Kawabata

Furuta²,

Shinozaki³

et al. 2002

Drug Metab Dispos

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ABSTRACT:To elucidate the transport system by which [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) is taken up into the liver, we investigated the uptake characteristics of Z-335 in isolated rat hepatocytes. In addition, we estimated the hepatic uptake of Z-335 in intact rats under steady-state conditions and compared it with the in vitro uptake clearance. Uptake of Z-335 is highly concentrative (cell-to-medium concentration ratios were 21.2 at 0.5 min and 71.7 at 5 min), temperature-dependent, and sensitive to metabolic inhibitors, indicating that uptake is mediated by energydependent uphill transport. In the presence of metabolic inhibitors [carbonyl cyanide p-trifluoromethoxyphenylhydrazone and rotenone], uptake remained at 37 and 49% of the control value, respectively, suggesting that ATP-independent uptake contributes to the total uptake of Z-335. The concentration dependence of the initial uptake velocity indicated a two-component process, one saturable component, with a K m value of 45.6 M and a V max value of 4.1 nmol/min/mg of protein, and a nonspecific diffusion clearance, with a P dif value of 8.3 l/min/mg of protein. The contribution of the carrier-mediated uptake to the total uptake in a linear range was estimated as 91%. The in vivo hepatic intrinsic clearance (CL int, app ) was comparable with that in vitro uptake clearance (PS influx ) and indicated that the CL int, app of Z-335 at steady state is rate-limited by the uptake process. In conclusion, hepatic intrinsic clearance of Z-335 at steady state is rate-limited by the uptake process since Z-335 is efficiently taken up by an active transport mechanism, followed by metabolism or biliary excretion.

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Transport and Binding of Methotrexate In Vivo

Cited by 143 publications

References 23 publications

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Application of the PKCYP-test to Predict the Amount of in Vivo CYP2C11 Using Tolbutamide as a Probe.

Carrier-Mediated Active Transport of a Novel Thromboxane A₂ Receptor Antagonist [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) into Rat Liver

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Transport and Binding of Methotrexate In Vivo

Cited by 143 publications

References 23 publications

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

Application of the PKCYP-test to Predict the Amount of in Vivo CYP2C11 Using Tolbutamide as a Probe.

Carrier-Mediated Active Transport of a Novel Thromboxane A2 Receptor Antagonist [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) into Rat Liver

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Carrier-Mediated Active Transport of a Novel Thromboxane A₂ Receptor Antagonist [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) into Rat Liver