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Biomedical subjects

W L Chiou

Publications and source records attributed to W L Chiou.

At least 19 recordsLinked to original sources
PubMed1992

Erythrocytes as a total barrier for renal excretion of hydrochlorothiazide: slow influx and efflux across erythrocyte membranes.

The potential barrier effect of erythrocytes (RBC) on renal excretion (mainly by tubular secretion) of hydrochlorothiazide (HCTZ) was evaluated in nine anesthetized rats during steady-state iv infusion. Drug concentrations in plasma and blood from the carotid artery and renal vein were assayed by a simple modified HPLC method. Renal extraction ratios were concentration-independent with a mean of 0.17 +/- 0.05 (SD). The renal excretion was found to occur primarily from the drug in plasma; the mean net fractional removal from plasma was 0.57 +/- 0.12, while that from RBC was less than 0.008 +/- 0.041. The virtual total unavailability of HCTZ from RBC (containing approximately 70% of drug in arterial blood) for renal excretion is attributed to relatively slow efflux of drug from RBC to plasma during each passage through the kidney compared with the blood transit time (in seconds). Preliminary in vitro influx and efflux kinetics of HCTZ across RBC membranes were studied using rat and human blood. The flux data could be adequately described by a linear, reversible, closed two-component system model, and the mean equilibration half-times (ET1/2) in rat and human blood were 10.9 and 20.5 min, respectively. The mean residence time of drug in blood circulation of rats was estimated to be 8.32 +/- 1.06 min, which is shorter than the ET1/2. This is consistent with data indicating that distribution equilibrium of HCTZ in arterial blood might not be reached in vivo even at steady state. Other implications of slow transport kinetics of drugs across RBC membranes are discussed.

Adult↗
PubMed1992

Large differences in the biological half-life and volume of distribution of hydrochlorothiazide in normal subjects from eleven studies. Correlation with their last blood sampling times.

In spite of more than three decades of wide use of hydrochlorothiazide as a diuretic, its mean biological half-life (t1/2) and apparent volume of distribution (Vdarea) in normal subjects were found to vary greatly among 11 studies reported between 1976 and 1986. For example, the mean t1/2 values ranged from 3.2 to 13.1 h and Vdarea values from 1.53 to 4.19 l/kg. Furthermore, a t1/2 of only 2.5 h and a Vdarea of only 0.83 l/kg were cited in a recent textbook. The present analyses show a positive correlation between the length of the last blood sampling time (tlast) employed and the t1/2 or Vdarea. The smaller t1/2 and Vdarea values reported were attributed to the insufficient length of time used in blood sampling for a drug exhibiting polyexponential disposition function. The kinetic and dynamic significance of the findings were briefly described.

Blood Volume↗
PubMed1979

Chlorpheniramine. I. Rapid quantitative analysis of chlorpheniramine in plasma, saliva and urine by high-performance liquid chromatography.

A method was developed for the rapid quantitative analysis of chlorpheniramine in plasma, saliva and urine using high-performance liquid chromatography. A diethyl ether or hexane extract of the alkalinized biological samples was extracted with dilute acid which was chromatographed on a reversed-phase column using mixtures of acetonitrile and ammonium phosphate buffer as the mobile phase. Ultraviolet absorption at 254 nm was monitored for the detection and brompheniramine was employed as the internal standard for the quantitation. The effects of buffer, pH, and acetonitrile concentration in the mobile phase on the chromatographic separation were investigated. A mobile phase 20% acetonitrile in 0.0075 M phosphate buffer at a flow-rate of 2 ml/min was used for the assays of plasma and saliva samples. A similar mobile phase was used for urine samples. The drug and internal standard were eluted at retention volumes of less than 17 ml. The method can also be used to quantify two metabolites, didesmethyl- and desmethylchlorpheniramine, in the urine. The method can accurately measure chlorpheniramine levels down to 2 ng/ml in plasma or saliva using 1 ml of sample, and should be adequate for biopharmaceutical and pharmacokinetic studies. Various precautions for using the assay are discussed.

Chlorpheniramine↗
PubMed1979

Creatinine VIII: saliva levels of endogenous "true" creatinine in normal subjects.

Concentrations of endogenous "true" creatinine in saliva and serum were measured in 6 normal subjects using a specific and sensitive high-performance liquid chromatographic method. There were marked intra- and intersubject variations in saliva levels during an 11-wk study. There were also large variations in the ratios of the saliva/serum creatinine level during the one-day study for all the subjects, the average highest intrasubject variation being 481% and the range being 128% to 816%. The average ratio of saliva/serum level was 0.0999 +/- 0.097 (CV = 97%); the highest saliva level was 1.5 mg%. Lower salivary levels were probably due to the extremely low lipid solubility of creatinine resulting in a relatively slower diffusion rate than of the transport of water into the saliva. Salivary monitoring of creatinine is concluded to be of little use in indicating its concentration in plasma or serum because, unlike many other substances it does not follow the pH-partition principle for saliva/plasma distribution.

Adult↗
PubMed1979

Fluorocarbon aerosol propellants XII: Correlation of blood level of trichloromonofluoromethane to cardiovascular and respiratory responses in anesthetized dogs.

Anesthetized mongrel dogs were exposed to various concentrations of trichloromonofluoromethane. Before, during, and after the inhalation, arterial and venous blood samples were obtained for fluorocarbon analysis. After the cessation of fluorocarbon inhalation, a multiexponential decline for the blood was observed. This finding was similar to that of previous study in which the fluorocarbon was administered intravenously to unanesthetized dogs. The half-life calculated from the terminal phase was about 280 min, and the pseudodistribution equilibrium was reached about 100 min after dosing. Study of the relationship between blood fluorocarbon levels and effects on the respiration rate and arterial blood pressure indicates that the sites of these pharmacological activities are located in the blood or central compartment rather than in the peripheral compartment. The effect on the heart rate appears to be quite instantaneous after inhalation. These results might shed some light on the fast effect of the fluorocarbon propellants, which caused sudden deaths after inhalation of a large quantity.

Aerosol Propellants↗
PubMed1979

Differential thermal, solubility, and aging studies on various sources of digoxin and digitoxin powder: biopharmaceutical implications.

Unlike most organic compounds, both digoxin and digitoxin melted over a wide temperature range, with the widest range being 88 and 33 degrees for both compounds, respectively. Furthermore, the melting ranges varied markedly among several untriturated powders obtained from commercial sources and after recrystallization. Trituration produced dramatically sharper and generally lower melting temperatures. Apparent equilibrium solubility also varied considerably among different untriturated compounds. Correlation between solubility and final melting temperature was found. Results from dynamic solubility studies were used to explain the failure of trituration to enhance the apparent equilibrium solubility in certain samples. Storage at room temperature increased the melting points and decreased aqueous solubilities. Several reasons such as the presence of polymorphic and amorphous forms, crystal defects, impurities, and solvate formation were postulated to explain the findings. In a preliminary study, the in vitro dissolution rates of two commercial tablet products stored at elevated temperatures for 4-8 weeks progressively decreased. Biopharmaceutical implications and areas for further studies are discussed.

Biopharmaceutics↗
PubMed1979

Rapid compartment- and model-independent estimation of times required to attain various fractions of steady-state plasma level during multiple dosing of drugs obeying superposition principle and having various absorption or infusion kinetics.

A new general equation based only on plasma data was derived for rapid estimation of the average plasma level and the mean fraction of the steady-state plasma level attained during any multiple-dosing interval. It can be applied to any complex absorption or infusion kinetics (i.e., is not limited to zero-order or first-order kinetics) for drugs obeying linear disposition kinetic or superposition principles. The time, t, required to reach a certain mean fraction of the steady-state plasma level is equal to the time at which the plasma area from time zero to time t is equal to the same fraction of the plasma area from time zero to infinity (AUC0 leads to infinity) following a single dose. No other pharmacokinetic parameters are necessary.

Humans↗
PubMed1979

Potential pitfalls in the conventional pharmacokinetic studies: effects of the initial mixing of drug in blood and the pulmonary first-pass elimination.

The classical concept of assuming that an i.v. dose instantaneously distributes into the central or plasma compartment is reviewed, as is the potential for pulmonary first-pass effect. Based on available literature, the concept is shown to lead to serious errors in estimating pharmacokinetic parameters, particularly for drugs with high clearance.

Animals↗
PubMed1979

Chlorpheniramine. II. Effect of the first-pass metabolism on the oral bioavailability in dogs.

The pharmacokinetics of chlorpheniramine has been studied in six dogs by following the time course of plasma concentration of the drug after intravenous and oral administration of its maleate salt in solution form. After intravenous dosing the decline in chlorpheniramine plasma concentration was typically biexponential. The drug distributed rapidly and extensively to the extravascular tissues. The mean distribution phase half-life was 12.5 min, and the mean apparent volume of distribution, Vdb, was 525% of the body weight in four dogs with normal hematocrits. The mean half-life of elimination was 1.7 hr. The percent absolute availability following oral administration of the drug in the aqueous solution form was found to be dose dependent. At 100-mg dose, in six dogs, an average of 36% of the orally administered dose was found to be systemically available. At 50-mg dose, in one of the four dogs studied, no measurable plasma levels of chlorpheniramine were obtained, and the average bioavailability was only 9.4%. The average availability in four dogs at 200-mg dose was 39.4%. Even at 200-mg oral dose, the dogs did not show any signs of sedation and remained alert all through the experiment. Saturable first-pass gut and/or hepatic elimination has been postulated. The possible implications of these findings on the therapeutic effectiveness of the usual dosing regimen of chlorpheniramine in dogs are discussed.

Administration, Oral↗