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Biomedical subjects

M L Chen

Publications and source records attributed to M L Chen.

At least 199 records · Page 11Linked to original sources
PubMed1983

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits after intravenous administration.

The pharmacokinetics of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX), a major metabolite, were investigated in rabbits after intravenous bolus injection and infusion using a specific HPLC assay. The arterial sampling (from the carotid artery) was used in all the studies since peculiar and significant arterial-venous differences in the plasma concentration of MTX and 7-OH-MTX were found following bolus administration of the drug. The disposition kinetics of MTX appeared polyexponential with a small terminal phase having a half-life of 10.2-27.5 hr. Extensive formation of 7-OH-MTX occurred at the two dose levels (15 and 50 mg/kg). Nonlinear disposition of MTX was reflected in several aspects of data analysis. A disproportionate increase in the AUC with dose was observed. An increase in dose not only reduced the mean total body clearance (7.49 vs. 4.26 ml/min/kg) and renal clearance (4.89 vs. 2.76 ml/min/kg), but also prolonged the mean residence time (26.2 vs. 43.3 min). The steady-state volume of distribution (Vss) of MTX was estimated to range from 0.16 to 0.25 L/kg. More than 90% of the dose was excreted as MTX and 7-OH-MTX within 8 hr after dosing. Renal clearances decreased with the increasing plasma levels, suggesting active tubular secretion as one of the excretion mechanisms. A similar pattern for renal clearance of 7-OH-MTX was obtained. Infusion studies of 7-OH-MTX revealed that this metabolite had a longer residence time and a larger Vss as compared with MTX, which were in accordance with its physicochemical properties. Essentially complete doses of 7-OH-MTX could be recovered in the rabbit urine.

Animals↗
PubMed1983

Clearance studies of methotrexate and 7-hydroxy-methotrexate in rabbits after multiple-dose infusion.

The concentration-dependent clearance of methotrexate (MTX) and its metabolite, 7-hydroxy-methotrexate (7-OH-MTX), was demonstrated in 5 rabbits using 7 infusion rates (10.5-323 mg/hr). Mean total body clearance (from 34.3 to 13.1 ml/min) and mean renal clearance (from 25.6 to 7.6 ml/min) of MTX were found to decrease with increasing steady-state plasma concentrations (from 5.1 to 412 micrograms/ml), whereas nonrenal clearances remained relatively constant. An essentially steady-state plasma level of 7-OH-MTX was achieved during each MTX infusion, and its renal clearance also decreased (from 37.3 to 6.5 ml/min) with increasing metabolite levels (from 1.8 to 293 micrograms/ml). Saturable renal tubular secretion appeared operative for both drug and metabolite since their renal clearance (based on the free drug) to inulin clearance ratios were much greater than unity and the ratios were markedly reduced in 2 rabbits after probenecid treatment. Plasma protein binding of MTX (56%) and 7-OH-MTX (49%) were independent of concentrations between 0.1 and 300 micrograms/ml. Negligible MTX metabolism was found in rabbit kidney homogenates, thus validating renal clearance measurement in the present study.

Animals↗
PubMed1982

Determination of tissue to blood partition coefficients in physiologically-based pharmacokinetic studies.

The partition coefficient between tissue and blood used in physiologically-based pharmacokinetic modeling analysis was investigated using the concept of clearance. New equations were derived and compared with previously reported equations in constant intravenous infusion and bolus injection methods. The importance of differentiating arterial from venous blood is discussed.

Infusions, Parenteral↗
PubMed1982

Arterial and venous blood sampling in pharmacokinetic studies: griseofulvin.

The pharmacokinetics of griseofulvin were evaluated simultaneously using both arterial and venous plasma in three dogs and one rabbit after a rapid bolus intravenous dosing. Initial arterial-venous ratios 20 sec after injection were the highest and ranged from 15- to 752-fold for dogs; the ratio was 3240-fold for the rabbit. Both curves decayed paralleling each other at the terminal phase with the venous levels higher than arterial levels by 14-43 and 8.4% for the dogs and the rabbit, respectively. The use of the instantaneous input principle was found to overestimate the total area under the plasma level-time curve by as much as 166%. An exponential term with a negative coefficient was used to account for the short and steep rising phase of plasma levels after injection. Detailed analyses showed significant differences in various calculated pharmacokinetic parameters based on arterial or venous data. The present study exemplifies the need for careful assessment and interpretation of classical pharmacokinetic parameters. It appeared that short intravenous infusion rather than the instantaneous or rapid bolus intravenous injection should be preferred for routine pharmacokinetic studies.

Animals↗
PubMed1982

Effect of arterial-venous plasma concentration differences on the determination of mean residence time of drugs in the body.

Using dogs or rabbits as model animals the effect of arterial-venous plasma concentration differences of propranolol, procainamide, griseofulvin, furosemide and theophylline on the determination of mean residence time (MRT) following intravenous administration was evaluated using standard methods. The MRT values calculated from femoral venous data were always higher (ranging from 1.5 to 109%) than those from femoral arterial data. The differences were mainly attributed to the additional residence time of drugs in the sampling tissue (leg). From a physiological point of view it appears generally more logical to assume that only the MRT calculated from arterial data using conventional methods represents the "true" MRT in the body. The potential pharmacokinetic significance of the present findings is discussed. New approaches, which eliminates the effect of arterial-venous plasma concentration differences on the MRT determination, are proposed.

Animals↗
PubMed1981

Sensitive and rapid high-performance liquid chromatographic method for the simultaneous determination of methotrexate and its metabolites in plasma, saliva and urine.

A simple and sensitive high-performance liquid chromatographic assay of methotrexate (MTX) and its two active metabolites, 7-hydroxymethotrexate (7-OH-MTX) and and 2,4-diamino-N10-methylpteroic acid (APA) in plasma, saliva and urine was developed. The method involved deproteinization with acetonitrile followed by addition of isoamyl alcohol and ethyl acetate. After extraction the sample was chromatographed on a cation-exchange column and monitored at 313 nm. The retention times were 5, 7 and 9 min and detection limits 20, 10 and 5 ng/ml for 7-OH-MTX, MTX and APA, respectively. For concentrations greater than 100 ng/ml one-step deproteinization of 0.1 ml sample with 0.25 ml acetonitrile was satisfactory for sample preparations. The method has been evaluated in samples from patients and rabbits receiving MTX.

Animals↗
PubMed1981

Instantaneous input hypothesis in pharmacokinetic studies.

Observed venous plasma concentrations of furosemide, propranolol, griseofulvin, and theophylline at 0.33 and 0.66 min after intravenous bolus injections to unanesthetized dogs were compared with those extrapolated using the instantaneous input hypothesis. At 0.33 min, extrapolated/observed plasma level ratios as high as 20.5, 65.5, 226, and 1.17 were found for these four drugs, respectively. Venous plasma levels peaked at 1 min postinjection in all studies. Total plasma areas (AUC0-->infinity) estimated using the instantaneous input principle were higher by as much as 6.0, 6.8, and 19.6% for propranolol, griseofulvin, and furosemide, respectively, when compared with experimental data. The effect on theophylline was negligible. These results suggest the need for cautious interpretation of some venous pharmacokinetic data. More studies in animals and humans are required to assess the magnitude of deviation from the instantaneous input hypothesis for drugs in general.

Animals↗
PubMed1981

Arterial-venous plasma concentration differences of six drugs in the dog and rabbit after intravenous administration.

The arterial blood from the femoral artery and venous blood from the femoral vein wee simultaneously collected following intravenous administration of propranolol, lidocaine, procainamide, furosemide, theophylline and griseofulvin to dogs or rabbits. The preliminary results of arterial-venous (A-V) plasma concentration profiles are reported in this communication. The maximum A/V ratios shortly after a rapid intravenous bolus dose were 277-, 15-, 34-, 33-, 5.4- and 3240-fold, respectively, for the above six drugs. The venous plasma levels were higher than arterial plasma levels during parallel terminal phase by as much as 104, 48, 134, 29, 16, and 47%, respectively, for the above six drugs. These data suggest a very rapid and extensive uptake of the drugs by the sampling tissues (the leg) shortly after dosing. The potential significance of A-V differences in pharmacokinetic and pharmacodynamic studies are briefly discussed.

Animals↗
PubMed1981

Pharmacokinetics of drugs in blood II. Unusual distribution and storage effect of furosemide.

Furosemide was found to exhibit both in vitro and in vivo unusual distribution kinetics in whole blood. For example, at an initial blood concentration of 10 microgram/ml, a 'trough' plasma level phenomenon occurring at 5 min was found in the in vitro study using blood from humans, rabbits, and dogs. A similar effect was also observed in rabbits following intravenous dosing. The effect of the time elapsed between blood collection and centrifugation on the measured plasma level, the so called 'blood storage effect' was clearly demonstrated in rabbit studies. A difference of up to 32% was found. Furosemide was found to be stable in blood, and the equilibrium plasma/blood cell concentration ratios were about 1.5-2.0 at 0.1-50 micrograms/ml in blood.

Animals↗