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W L Chiou

Publications and source records attributed to W L Chiou.

At least 37 records · Page 2Linked to original sources
PubMed1996

New perspectives on the theory of permeability and resistance in the study of drug transport and absorption.

Permeability coefficient (P) expressed as distance per unit time has been commonly interpreted to represent the velocity of drug movement across a heterogeneous medium such as skin and intestinal epithelium. The basis of such an interpretation is questioned on several grounds. For example, the basic assumption for calculating P (as defined conventionally) according to the Fick's law of diffusion requires the entire medium to be homogeneous and rate-limiting in transport. The theoretical basis of the widely used total resistance or resistance additivity concept is reviewed. Such a concept is shown to be applicable to the study of total transit time across the medium but may not be applicable to the study of steady-state flux or absorption across the medium under normal conditions. Based on the diffusional, compartmental, absorptive clearance or carrier-mediated-transport analysis it is shown that only the first transport resistance from the bulk medium across the surface (such as cellular membranes) of the permeation medium (such as a cell or a tissue) is usually the deciding factor in drug transport or absorption. Resistances on the other side of the surface barrier usually only affect the drug accumulation vs. time profile in the medium, but not the steady-state flux or absorption. The role of unstirred water layer adjacent to the internal capillary wall is postulated to play an important role in causing the blood-flow dependency in absorption, a phenomenon that cannot be rationalized by the conventional effective permeability concept. The conventional concept of sink conditions on the serosal side is questioned. The present analysis further supports the use of the absorptive or transport clearance concept in absorption or transport study. Effective permeability is regarded as a mathematical operator for transport across a barrier or a tissue, and may be unrelated to the Fick's law of diffusion under most conditions. The velocity unit for P is regarded simply as a "collapsed" unit based on the absorptive or transport clearance per unit gross surface area. It is hoped that this commentary will stimulate further research and discussions in this general area of drug transport and absorption. It appears that there is a need to experimentally confirm the total resistance theory in biological systems.

Cell Membrane Permeability↗
PubMed1995

We may not measure the correct intestinal wall permeability coefficient of drugs: alternative absorptive clearance concept.

It is shown that the conventional method (based on the thin-wall membrane theory) of studying the rate of disappearance or absorption from the lumen alone may not yield the correct intestinal wall (membrane) permeability coefficient of drugs. Potential reasons for causing this problem such as first-pass metabolism and accumulation of drugs in gut wall or tissue as well as back diffusion of drugs from the gut tissue to the lumen (i.e., a part of exsorption phenomenon) and potential major transport barriers across the protoplasm, basal membrane, and basement membrane are discussed. Contrary to the conventional concept, basal and basement membranes should also be considered major barriers for absorption into the blood for compounds with low intestinal permeability, and the protoplasm or cytoplasma should also be considered a major absorption barrier for compounds with high intestinal permeability. Strictly speaking, the conventional experimental method cannot be considered a bona fide method for studying drug permeability that deals with the movement of drug molecules from one side to the other side of a membrane, cell, medium, or device. The wall permeability coefficient thus obtained may therefore not represent the true wall permeability coefficient. "Intestinal absorptive clearance per unit gross surface area" is advocated as the best alternative term because it should more accurately reflect the true meaning of an experimental result for any compounds studied. In contrast to conventional cylindrical, unstirred tube models for the determination of wall permeability coefficients, the absorptive clearance calculation can be made based on a physiologically more realistic model-independent, "flat" or "distended," stirred (not well-stirred) intestinal model. Two model-independent terms, "effective intestinal permeability coefficient" and "effective absorptive permeability coefficient," are recommended as the second alternatives. These terms are theoretically valid for compounds that are not metabolized in the intestinal tissue; they represent the overall permeability across the intestinal tissue (from lumen to blood) under given experimental conditions. Potential shortcomings of using dimensionless wall permeability in the conventional absorption modeling are also discussed.

Animals↗
PubMed1995

First-pass accumulation of salicylic acid in gut tissue after absorption in anesthetized rat.

PURPOSE: The purpose of this paper is to report the study on the first-pass accumulation kinetics of salicylic acid (SA) in gut tissue after absorption by simultaneously analyzing drug contents in the lumen, gut tissue, and blood in anesthetized rats. METHODS: Sodium salicylate (5.4 mg as SA) in 0.4 ml normal saline was administered into a closed 10-cm jejunal loop. Drained mesenteric blood from the loop area was collected every minute, while lost blood was replaced through infusion of oxygenated blood from donor rats. At 3, 10, 20, 40, or 60 min after dosing, SA remaining in lumen, accumulating in gut tissue, and appearing in blood were analyzed by HPLC. All the data were fitted into a linear two-consecutive (lumen and gut tissue) first-order kinetic model. RESULTS: After absorption, significant amounts of SA accumulated in gut tissue before appearing in blood, e.g., at 3 or 20 min after dosing, 74.4 or 54.4% of absorbed SA accumulated in gut tissue, respectively. Practically all administered SA was recovered. The estimated mean absorption time from the lumen and mean transit time in gut tissue of SA were 20.4 and 18.5 min, respectively. CONCLUSIONS: The above results indicate that gut tissue may act as a reservoir for drug accumulation during the first pass after oral absorption. Thus, the rate of transport of drug into blood circulation after oral administration may significantly differ from the true rate of absorption through the gut membrane. The potential transport resistance from gut tissue to blood should probably be considered in the modeling of GI absorption.

Animals↗
PubMed1994

Effect of 'unstirred' water layer in the intestine on the rate and extent of absorption after oral administration.

The presence of an aqueous diffusion layer or 'unstirred' water layer adjacent to the intestinal membrane has long been regarded as a potential barrier for intestinal absorption of compounds. Theoretical analyses were performed in the present study to quantitatively determine the effect of this layer on the rate and extent of absorption of passively absorbed compounds with different membrane absorption half-lives (10 to 300 min) in humans, dogs, rabbits, rats and mice. Diffusion half-lives across this (40 microns thick) layer were estimated to be 5.8, 2.5, 1.1, 0.65 and 0.32 min, respectively, in the distended intestine of the above five species. These half-lives are reduced by about 5-fold when the intestine is about 80% 'flat' in fasting state. The results of extensive analysis indicate that the presence of such a layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption. The study also indicates that an aqueous layer of 708 microns has practically no effect on the extent of absorption of progesterone, a highly lipophilic compound, in rats. For prediction of or correlation with the fraction of oral dose absorbed after oral administration, the present study indicates that use of apparent or effective permeability rather than unbiased or true wall (membrane) permeability, as advocated earlier by others, should generally suffice.

Administration, Oral↗
PubMed1994

Determination of drug permeability in a flat or distended stirred intestine. Prediction of fraction dose absorbed in humans after oral administration.

Equations published earlier to calculate intestinal permeability (P) from in situ or in vivo studies and to predict fraction of dose absorbed (F) after oral administration may often be based on some physiologically and pharmacokinetically unrealistic assumptions; for example, (a) the intestine behaving like a "fully" distended, rigid, cylindrical tube without any intrinsic motility or stirring, (b) no accumulation of drug in gut wall or tissue, (c) lack of blood flow effect on permeability, (d) lack of back diffusion from absorptive cell to lumen, (e) a smooth surface area for absorption, and (f) a well-defined luminal concentration profile. An alternative, simple, realistic organ clearance approach is described here to re-define and calculate P as apparent absorptive permeability or absorptive clearance per unit gross surface area and to predict F based on either human or animal data. The approach may prove particularly valuable in view of the insignificant impact of "unstirred" water layer on F. The small intestine in humans and animals is found to be very flat overall (only about 10 of 30% distension in fasting state). The human intestinal luminal flow after normal dosing is estimated at about 3 ml/min, sixfold higher than 0.5 ml/min proposed by others. The direct consequence of an early assumption that dimensionless P is the same between human and rat is pointed out; the permeability coefficient being 7-10 times higher in rats than in humans, that is, however, not supported by experimental data. The apparent success of a widely used approach to estimate F based on rat data is rationalized.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Intravenous verapamil kinetics in rats: marked arteriovenous concentration difference and comparison with humans.

The pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague-Dawley rats following i.v. administration at a dose of 1 mg kg-1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed-phase high-performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large Vdss (2.99 +/- 0.57 l kg-1) and Vd beta (5.08 +/- 0.54 l kg-1). The apparent terminal plasma T1/2, MRTiv, and CLp were 1.59 +/- 0.46, 1.26 +/- 0.12 h, and 40.4 +/- 9.73 ml min-1 kg-1, respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and Vdss, and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo. The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T1/2 or CLp and the advantage of using CLu (unbound plasma clearance) in interspecies scaling is also discussed.

Animals↗
PubMed1993

Intrahepatic distribution of hydrochlorothiazide and quinidine in rats: implications in pharmacokinetics.

The intrahepatic distributions of a nonmetabolized drug, hydrochlorothiazide (HCTZ) and a highly metabolized drug, quinidine (QD), were studied separately in five anesthetized rats during steady-state intravenous infusion. Liver samples (20-24) from various parts (0.1-0.2 g each) at the end of infusion were collected from each rat and analyzed for drug concentration by HPLC. The distribution of HCTZ in various macro regions appears quite "homogeneous," with a CV of drug concentration for each rat ranging from 2.6 to 4.7% (grand mean, 3.7 +/- 0.8%), whereas that of QD seems less "homogeneous," with a CV ranging from 8.5 to 28.3% (grand mean, 15.6 +/- 7.7%). The above results indicate that drugs that are not complicated by hepatic metabolism may tend to show more "homogeneous" distribution and those that are highly metabolized and/or known to strongly bind to hepatic tissue component(s) may show less "homogeneous" distribution. The results from the present QD study are in contrast with the general, much more heterogeneous distribution found in an isolated in situ perfusion study reported earlier. The implication of the present study in physiological pharmacokinetic and hepatic modeling is discussed.

Animals↗
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↗
PubMed1990

Analysis of drugs and other toxic substances in biological samples for pharmacokinetic studies.

The importance of the role of analysis of drugs and other toxic substances in biological samples (bioanalysis) in medicine, toxicology, pharmacology, forensic science, environmental research and other biomedical disciplines is self-evident. Among these disciplines, bioanalysis plays a special pivotal role in pharmacokinetics. The pharmacokinetic parameters, such as half-life, volume of distribution, clearance and bioavailability, of drugs and other compounds are derived from the concentrations of these analytes assayed in the biological samples collected at specified time points. The capability of analysts to develop sensitive and specific analytical methods for the assay of low concentrations of drugs and other toxic compounds in small amounts of biological samples has contributed significantly to the theoretical advances in pharmacokinetics and its applications in clinical pharmacology and the management of drug therapy in patients. The increased demands for pharmacokinetic applications in turn have stimulated the innovation and improvement in bioanalytical technologies. The reliability of the pharmacokinetic conclusions depends on the accuracy and precision of the analytical methods employed to assay the biological samples. Factors that affect the integrity of the bioanalytical data should therefore be controlled in analysis of biological samples for pharmacokinetics studies. The biological samples for drug concentration determination should be collected as specified in the study protocol with respect to the time and site of sampling. These samples should be processed to avoid extraneous interactions between the analytes and sampling devices or additives resulting in the redistribution of the analytes between components of the biological samples, such as displacement of drug binding and changes in the distribution of the analytes between plasma and red blood cells. The stability of the drugs and other analytes in the samples should also be evaluated to establish the conditions suitable for the transportation and storage of the samples to avoid chemical, photochemical and enzymatic degradation of the analytes. Various technologies have been utilized to assay biological samples for pharmacokinetic studies. The most frequently used are chromatography (high-performance liquid chromatography, gas chromatography and thin-layer chromatography), immunoassays and mass spectrometry.(ABSTRACT TRUNCATED AT 400 WORDS)

Body Fluids↗
PubMed1990

Marked heterogeneity in the intrahepatic distribution of quinidine in rats: implications in pharmacokinetics.

Approximately 20 to 24 samples (0.1-0.2 g each) were obtained from each of six isolated rat livers following steady-state infusion of quinidine. The concentrations of quinidine, analyzed by an HPLC method, were found to vary markedly within each lobe (up to approximately 52-fold) or between lobes (up to approximately 25-fold) from the same liver. The maximum intrahepatic concentration difference in the six livers studied was 208-fold. Implications of the present study in the determination of liver drug concentration, and of the partition coefficient between liver and venous drug concentration in physiological pharmacokinetic modeling, as well as in hepatic modeling, are discussed.

Animals↗
PubMed1989

Effect of a change in the luminal perfusion rate on intestinal drug absorption studied by a simple unified organ clearance approach.

A recently proposed simple, noncompartmental, unified organ clearance approach was employed to study the effect of change in luminal perfusion rate (Q) on the steady-state intestinal absorption extraction ratio (E) of drugs. The equation used for correlation or prediction is E = H/(Q + H), where H is the apparent intrinsic intestinal absorption clearance of drug and assumed to be constant under linear conditions. Reported experimental data from intestinal perfusion studies in rats were used to evaluate the applicability or accuracy of the above equation. It was found that the mean difference between the predicted and the reported E values for seven steroids with a very wide range of partition coefficients between n-octanol and water (P) was 4.37% as Q was reduced from 0.497 to 0.247 ml/min. Reported changes in E due to multiple variation in Q (up to about 10 times) for hydrocortisone, progesterone, and iopanoic acid were satisfactorily predicted. The relationship between H and log P and the potential limitation of the present absorption approach are discussed. The present limited study also indicates that the absorption of the steroids with higher lipophilicity is usually less flow dependent.

Animals↗
PubMed1989

Erythrocytes as barriers for drug elimination in the isolated rat liver. II. Propranolol.

The potential of erythrocytes (RBC) to serve as "barriers" of hepatic elimination of propranolol, a drug with rapid equilibration in blood, was studied in rats under two conditions: (I) the drug was preequilibrated in blood before infusion into the liver, and (II) the drug was directly infused into the liver. The mean fractions of dose escaping elimination during each pass under conditions I and II were 0.0561 +/- 0.040 and 0.0290 +/- 0.024, respectively (P less than 0.02). Contrary to the early study on doxorubicin, most drug molecules in RBC were found to be available for elimination. Implications of the present findings in the prediction of hepatic first-pass effect after oral administration, on the basis of intravenous data, are discussed. Marked underestimation of oral bioavailability of propranolol in humans is consistent with the RBC "barrier" effect hypothesis.

Animals↗
PubMed1989

Erythrocytes as barriers for drug elimination in the isolated rat liver. I. Doxorubicin.

The effect of doxorubicin (Dx) equilibration between plasma and erythrocytes (RBC), prior to entering the liver, on hepatic elimination was evaluated under two conditions: (I) the drug being first equilibrated for 30 min in the perfusate (containing 27% human RBC) before infusion into the liver and (II) the drug being directly infused into the liver. Mean (N = 6) steady-state hepatic extraction ratios (E) under conditions I and II were 0.286 +/- 0.131 (SD) and 0.592 +/- 0.147, respectively. The marked difference in E was attributed mainly to the initial difference in plasma/RBC Dx distribution ratio of the inlet blood, the slow efflux of Dx from RBC into plasma under condition I, and the slow influx of Dx from plasma to RBC under condition II. The results indicate that most Dx molecules in RBC are not available for elimination. Drug equilibration between plasma and RBC may therefore represent an important factor in hepatic first-pass metabolism.

Animals↗
PubMed1989

The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I).

At least 42 compounds have been reported to exhibit significant or marked blood sampling site dependence in concentration after dosing in humans and animals. The very high efficiency of uptake of drug by the poorly perfused sampling tissue (e.g. arm or leg) during its very short transit through the capillary (1 to 3 seconds) is mainly responsible for such a universal phenomenon. When marked arteriovenous concentration differences exist, their entire plasma (blood or serum) concentration-time profiles may resemble those obtained from completely different drugs or from different dosing rates. After an intravenous bolus injection, the reported maximal arteriovenous differences were 3240-fold for griseofulvin during the early distribution phase (arterial concentration being higher than venous, and 234% for procainamide during the terminal phase (venous concentration being higher). The reported maximal steady-state arteriovenous difference during infusion was 3.8-fold for glyceryl trinitrate (nitroglycerin), with the arterial level higher, due to metabolism and possible strong binding by sampling tissue. Interestingly, peak arterial plasma concentrations were usually achieved at about 0.5 minutes, while peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection. Thus, the plasma concentration-time profile after an intravenous bolus injection actually resembles that predicted for a short term intravenous infusion, according to the classical instantaneous input hypothesis. Potential factors that may affect the degree of arteriovenous difference are here reviewed in detail. The implications of potential marked arteriovenous differences in pharmacokinetics, in pharmacokinetic/pharmacodynamic correlations or modelling, in toxicology, and in drug therapy are extensively discussed. Clinicians or scientists dealing with the determination and/or use of plasma concentration data should be fully aware of this problem. Many previous studies, based on the commonly accepted assumption that immediately or shortly after dosing plasma (blood) concentrations are essentially uniform throughout the blood circulation or the central (plasma) compartment, may require a reexamination. This is particularly important since the 'driving force' for distribution of a drug to various parts of the body for elimination, for accumulation or for producing a pharmacological or toxic effect, is its concentration in arterial blood, and not in venous blood drained from a poorly perfused tissue (venous blood may more accurately reflect drug concentrations in the poorly perfused sampling tissue itself). The present review probably represents the first of its kind ever reported in the literature. It is hoped that the review will increase the awareness of this very fundamental and important subject matter among our readers, and may also stimulate further studies or discussions.

Animals↗