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Biomedical subjects

W L Chiou

Publications and source records attributed to W L Chiou.

At least 73 records · Page 4Linked to original sources
PubMed1983

Evaluation of potential causes for the incomplete bioavailability of furosemide: gastric first-pass metabolism.

Potential causes for reported incomplete (usually 40-60%) and often highly variable (e.g., 11-79%) bioavailability of furosemide in humans were investigated. The drug was found to be fairly stable in gastric fluids and its hepatic first-pass elimination (HFPE) was estimated to be much less than 6% based on published i.v. data. The rat was used as the main model for extensive evaluation. About 4% (n = 4) of dose was recovered unchanged in the GI tract after i.v. injection while about 40% (n = 12) was recovered after a 120-fold (0.05-6 mg) dose range of oral administration. In another study 70% of the oral dose eventually disappearing (presumably due to absorption and first-pass elimination) from the GI tract was estimated to occur in just 20 min. These data indicate an unsaturable, incomplete, site-specific absorption as well as a lack of dissolution-rate-limited absorption at the doses studied. Based on plasma data, oral bioavailability in four rats was only 30%, and the HFPE much less than 10%. After oral administration, 61% of the dose was absorbed and/or metabolized in the GI recovery study. Thus, 20-30% of oral dose in rats must be metabolized in the GI wall during absorption. The metabolic activity of stomach (homogenate) from 5 rats was found to be much (e.g., 5-10.5-fold) greater than those of liver and small intestine. This was also confirmed in preliminary studies with 3 rabbits and 1 dog. Large intersubject variability in enzyme activity was found in rats and rabbits. The phenomenon of a presystemic first-pass effect was also substantiated by urinary excretion data of a metabolite. It is postulated that variable gastric and intestinal first-pass metabolism may be a major factor causing incomplete and irregular absorption of furosemide in humans.

Administration, Oral↗
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↗
PubMed1983

Exposure of hospital workers to airborne antineoplastic agents.

Practices for handling antineoplastic drugs were surveyed, and ambient-air sampling for four antineoplastic agents was conducted in outpatient oncology clinics. A questionnaire was administered in 1981 to the nurse or pharmacist in charge of drug preparation at 10 hospital oncology clinics. At three sites, air samples were collected during working hours in medication-preparation rooms and nearby offices. The air-sampling pumps contained filters at breathing-zone height; room air was drawn through each filter for 40 hours. Extracts from the filters were assayed by high-performance liquid chromatography (HPLC) for fluorouracil and cyclophosphamide in seven sets of samples and methotrexate and doxorubicin in five sets of samples. Mass spectrometry (MS) was used to confirm detection of fluorouracil. Total use of each monitored drug was recorded at each site. Nine clinics had no ventilation hood, and drugs were prepared by nurses in eight clinics. Routine use of gloves (three clinics) and masks (one clinic) was uncommon, and wastes were disposed of in uncovered receptacles in four of the clinics. Eating and drinking occurred in seven of the preparation rooms. At the main air-sampling site, fluorouracil (0.12-82.26 ng/cu m) was detected in air during 200 of the 320 hours monitored. Cyclophosphamide (370 ng/cu m) was present during 80 hours. In the two other sites, fluorouracil was detected by HPLC but not confirmed by MS, and no cyclophosphamide was detected. No detectable amounts of methotrexate and doxorubicin were present. Fluorouracil was the most frequently used drug, and cyclophosphamide was second. Results suggest that personnel handling antineoplastic drugs are subject to potential systemic absorption of these agents by inhalation.

Air Pollutants, Occupational↗
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

Pharmacokinetics of chlorpheniramine after intravenous and oral administration in normal adults.

Plasma and urinary levels of chlorpheniramine (CPM) and its 2 demethylated metabolites were measured by HPLC after i.v. and oral dosing. In 5 mg (maleate) i.v. bolus studies in 2 subjects, plasma CPM levels were fitted to triexponential equations with terminal half-lives (t 1/1) of 23 and 22 h and area of 3.6 and 3.21/kg, respectively. Intravenous data predicted hepatic blood extraction ratios for the 2 subjects to be 0.06 and 0,07, respectively. Absolute bioavailability from oral solution (10 mg) was 59 and 34%, and from tablets (8 mg) 44 and 25%, respectively, indicating extensive gut first-pass metabolism. Mean t 1/2 from 7 oral fasting studies in 5 subjects was 28 h (19-43 h). Mean absorption lag time was 0.7 h (0.4-1.3 h), and mean peak time was 2.8 h (2-4 h). In 2 subjects, 6 mg solutions were given every 12 h for 9 doses; good correlation between single and multiple dose kinetics was found. Significant accumulation was demonstrated in simulation studies with frequent daily dosing. Estimated accumulation ratios vary from 4.1 to 9.4 (mean 6.5). The t 1/2 from urinary data (collected for 12 days) was consistent with plasma data. The above results suggest the need to reexamine the current practice of frequent daily dosing and the use of sustained or controlled release dosage forms of this drug. The possible cause of reduced plasma clearance of CPM in renal patients is discussed.

Administration, Oral↗
PubMed1982

The physiological significance of total body clearance in pharmacokinetic studies.

The significance of the total body clearance (CL) is studied based on a physiological pharmacokinetic model. In the absence of evidence to the contrary, and for the sake of uniformity, it is proposed that the elimination rate of a drug at any time after various routes of dosing be assumed to be proportional to its systemic arterial plasma (blood) concentration with a proportionality constant equal to CL. The CL, calculated by the intravenous dose divided by the AUC, is defined as the hypothetical volume of the systemic arterial plasma (blood) completely cleared of drug per unit time even though the drug is eliminated by the lungs and venous plasma is assayed. A marked difference in the calculated elimination rate of lidocaine in patients based on arterial or venous plasma data is demonstrated. The calculated CLs which are sometimes greater than the cardiac output can be rationalized. The limitation of conventional multicompartmental mammillary modelling theory in the defining of CL is discussed.

Humans↗
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↗
PubMed1982

The significance of the arterial-venous plasma concentration difference in clearance studies.

Arterial-venous blood or plasma concentration differences and their implications for renal clearance studies are reviewed. In common practice peripheral venous blood or plasma is used for absolute clearance studies employing timed-interval methods following single dosing. However, this is theoretically inappropriate or incorrect because of the systemic arterial-venous blood or plasma concentration difference. Many examples showing arterial-venous differences, together with brief theoretical discussions of factors affecting the differences, are presented. The implications in clearance studies of other organs such as lungs, liver, and the gastrointestinal tract are also discussed.

Arteries↗
PubMed1982

New physiologically based methods for calculating the apparent steady-state volume of distribution in pharmacokinetic studies.

Based on the compartment- and model-independent or physiologically based clearance approaches, general equations to calculate the apparent steady-state volume of distribution of compounds (Vdss) are derived. The results show that either arterial plasma level data or the combination of venous plasma level data and cumulative urinary excretion data after a bolus or intravenous infusion can be used to calculate the Vdss. In view of the potential marked arterial-venous plasma concentration difference, and of the fact that the driving force for elimination and distribution should generally be the drug concentration in the arterial plasma use of venous data to calculate the Vdss as is commonly performed is inappropriate.

Humans↗