Biomedical subjects
Publications and source records attributed to W L Chiou.
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The applicability of a simple noncompartmental organ clearance approach was extended to evaluate the effect of change in blood flow (Q) on hemodialysis clearance (CL) using patient data reported in the literature. Hemodialysis blood or plasma clearance data of vitamin B12, urea, creatinine and uric acid were fitted into the equation, CL = HQ/(Q + H), where H is the apparent intrinsic hemodialysis clearance for total (bound and unbound) compound. The Q values varied up to 16-fold. The extraction ratios ranged from about 0.4 to 1.0 (indicating existence of marked concentration gradient) and 0.1 to 0.6 for urea and vitamin B12, respectively. The H only serves as an "operator" in a given system, and the H value per unit length of the dialyzer coil can be shown to increase markedly with the length of coil, which is different from the basic assumption in the well-stirred model. For vitamin B12 the present clearance approach appears to be slightly superior to the "parallel-tube model".
Unbound plasma clearances (CLu) in humans and rats of 15 extensively metabolized drugs (phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, amobarbital, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam), studied earlier by Sawada et al. (J. Pharmacokin, Biopharm. 13:477-491, 1985), were calculated. It was found that the ratio of CLu per square meter of body surface area between human and rat ranged from 0.38 for pentobarbital to 2.34 for tolbutamide, with a mean ratio of 1.07. When body weight (BW) was used for correlation, the mean CLu was proportional to BW 0.657 +/- 0.0935. A rationale for the above empirical findings is postulated. The present study seems to indicate the existence of a general similarity or predictability in the CLu of drugs between rats and humans. Low correlations were generally obtained when total (bound and unbound) plasma clearances were used for comparison.
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The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when the doses were related to unit body surface area (BSA) but not on unit body weight, indicating similar interspecies absorptive capacity in terms of unit BSA. This finding may be partly rationalized by marked similarities in the reported solution transit time (2-3 hr) in the small intestine as well as in the calculated gross surface area of the small intestine per unit BSA (0.163 for rat and 0.132 for human). Contrary to the previous postulation of a specific absorption site, the drug was absorbed from different regions of the GI tract with apparent 1-hr absorption rates, studied by the in situ closed-loop method, in the following rank order: jejunum (34.6%) greater than duodenum (32.7%) greater than large intestine (20.1%) greater than ileum (18.0%) greater than stomach (12.4%). Different from the commonly assumed first-order absorption process, the intestinal loop absorption was concentration-dependent, suggesting a saturable mechanism. For example, the absorption rate at 0.008 mg/mL was higher than that at 0.2 mg/mL in ileal loops (61%, p less than 0.01) and jejunal loops (22%, p less than 0.1). In addition, the absorption rates at pH 6 and 7.4 were statistically identical, indicating a lack of ionization effect that is important in the passive absorption process. The solubility-limited absorption could probably be ruled out at doses below 2.55 mg/kg for rat and 125 mg for human in view of higher aqueous solubilities at 37 degrees C (e.g., 1.3 mg/mL at pH 7) found in the present study. Contrary to the previous hypothesis of low membrane permeability as a limiting factor for absorption, the "intrinsic" partition coefficient in 1-octanol/aqueous buffer was moderate, 0.6. Furthermore, the absorption in ileal and jejunal loops was enhanced by an apparent increase in mesenteric blood flow by caffeine. The existence of prolonged oral absorption in rats and humans is discussed.
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Published data on the effect of albumin binding on hepatic extraction of diazepam in isolated perfused rat livers were analyzed by a simple universal organ clearance approach proposed earlier by this author. Apparent hepatic intrinsic clearance of free (unbound) diazepam was found to decrease 39-fold from 334 ml/min in the absence of albumin to only 8.6 ml/min when the fraction unbound was reduced to 0.052. This interesting finding is rationalized by adsorption of albumin onto the surface of liver cells which might temporarily bind the drug molecules and slow down their diffusion across the membrane. A term "relative permeability" was introduced.
Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II-IV were essentially the same, but about 20% higher than those in treatment I. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I-IV, respectively. Except for treatment III, diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.
After entering the renal tubular lumen either through glomerular filtration or tubular secretion, drug molecules are considered to be removed from there by two competing processes: tubular fluid flow for urinary excretion and tubular reabsorption into blood circulation. The relative overall magnitude of the "force" or "efficiency" of these two processes will determine the fraction of drug molecules to be either excreted or reabsorbed, and hence their renal clearance (CLr). Urine flow rate (Q) is assumed to be proportional to the mean flow rate of tubular fluid at reabsorption sites (mainly in distal tubules), and used as an index to indirectly estimate the relative reabsorption "force" or "efficiency" (this may also be called apparent intrinsic reabsorption clearance). With the above assumptions, a plot of 1/CLr vs. 1/Q should yield a straight line under apparent first-order conditions. This has been confirmed for urea, theophylline, ethanol, chloramphenicol, amobarbital, riboflavin and fluoride based on human and dog (riboflavin only) data reported in the literature. Assuming that tubular reabsorption occurs only through the diffusion of unionized molecules, a plot of 1/CLr vs. fn/Q should also yield a straight line for weak acids and weak bases under linear conditions; the fn is the mean fraction of drug present in the unionized form at reabsorption sites whose mean pH is approximated or reflected by the urinary pH. The above straight line plot has been confirmed with human data for phenobarbital as well as human and rat data for salicylic acid. The effect of urine pH on biological half-life of pseudoephedrine in humans has also been successfully characterized.(ABSTRACT TRUNCATED AT 250 WORDS)
The method of Chiou to rapidly estimate theophylline total body clearance using two serum concentration data during the early stage of intravenous aminophylline infusion was evaluated in 16 patients with acute exacerbation of asthma or chronic obstructive pulmonary disease. The observed serum concentrations at later times were compared with those predicted. The mean prediction error for serum concentrations was 4.93% with a standard deviation of 20.06%. These results indicate that this simple method of Chiou may offer a reliable rapid estimation of total body clearance for dosage individualization in patients receiving intravenous aminophylline infusion.
The effects of urine flow and pH on methotrexate renal clearance were studied in seven conditioned male Beagle-Mongrel dogs. Steady-state plasma methotrexate and inulin concentrations were achieved by i.v. infusions preceded by i.v. bolus doses. Plasma and urine concentrations of methotrexate were quantitated by a sensitive high-performance liquid chromatographic assay, while those of inulin were measured by a colorimetric method. Since plasma protein binding of methotrexate was pH and concentration independent, methotrexate/inulin renal clearance without correcting for plasma binding was used for most of the data analyses. The results showed that the renal clearance ratios at the plasma methotrexate levels (approximately 0.1, 1.0, 20.0 and 100 micrograms/ml) studied remained relatively constant when urine pH (differences of up to about 2.5 units) and flow rate (differences of up to approximately 30 times) were changed. This indicated that renal reabsorption of methotrexate in these dogs was negligible. However, concentration-dependent renal clearance was observed. The mean renal clearances were 3.84, 3.94, 2.73, and 2.72 ml/min/kg at plasma concentrations of about 0.1, 1.0, 20.0, and 100.0 micrograms/ml, respectively, when urine was alkalized by sodium bicarbonate. The corresponding clearances were 4.02, 4.28, 2.62,and 2.65 ml/min/kg when urine was acidified by ammonium chloride. These showed the existence of saturable tubular secretion of methotrexate. No 7-hydroxy-methotrexate, a metabolite found in other species, was detected in the urine and plasma of the dogs.
Plasma, renal, and nonrenal clearances of methotrexate as well as their interrelationship were studied in five conditioned male beagle-mongrel dogs using the multiple-rate infusion method. Steady-state plasma methotrexate concentrations of 1, 20, and 100 micrograms/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused to study the effect of acid-base imbalance on the clearances. NaCl solution (0.9%) infusion served as a control. Plasma and urine concentrations of methotrexate were quantitated by a sensitive high-performance liquid chromatographic method. Distortion of body acid-base balance did not significantly change the clearances of methotrexate. The results showed that the plasma clearance (4.02 to 4.68 ml/min/kg) of methotrexate was relatively constant over the concentration range studied. The renal and nonrenal clearances, on the other hand, were concentration dependent. As the plasma methotrexate concentration increased from 1 to 20 or 100 micrograms/ml, renal clearance decreased from 3.60 to 4.28 ml/min/kg to 2.62 to 2.73 ml/min/kg, and nonrenal clearance increased form 0.35 to 0.42 ml/min/kg to 1.38 to 1.74 ml/min/kg. Concentration-dependent renal clearance may be due to saturation of the process involving active tubular secretion of methotrexate.
A simple, rapid and micro high-performance liquid chromatographic method was developed for separate or simultaneous determination of p-aminohippuric acid and iothalamate in plasma and urine using p-aminobenzoic acid as an internal standard. The method involved deproteinizing samples with two volumes of acetonitrile followed by injection of 5 microliters of deproteinized supernatant onto a C18 reversed-phase column. The mobile phase contained 3.5% acetonitrile in 0.04% phosphoric acid and flowed at a rate of 1.5 ml/min. The column effluent was monitored by an ultraviolet detector at 254 nm. Retention times for p-aminohippuric acid, iothalamate and p-aminobenzoic acid were approximately 4.5, 6 and 8 min, respectively. This method requires as little as 5 microliters of sample and can be used to measure accurately down to 1 microgram/ml p-aminohippuric acid and 0.5 microgram/ml iothalamate in plasma samples. The coefficients of variation of the assay with or without the use of internal standard were generally low (below 7%). No interferences from endogenous substances or any drugs tested were found.
The effects of plasma concentration and pH on the steady-state volume of distribution, Vss, of methotrexate (MTX) were studied in five conditioned male beagle-mongrel dogs. Steady-state plasma MTX concentrations of approximately 1, 20, and 100 micrograms/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused for the purpose of inducing plasma pH change, while the infusion of an isotonic solution of sodium chloride served as a control. Plasma and urine concentrations of MTX were quantitated by a sensitive high-performance liquid chromatographic method, and the Vss of MTX was estimated by a recently reported physiologically based method of Chiou and Lam. Statistically significant (p less than 0.05) concentration and plasma pH dependent Vss of MTX were observed. Concentration dependence of Vss was noted in sodium chloride and ammonium chloride infused dogs, but not in bicarbonate treated dogs. There was an average 50.0 and 44.8% increase in Vss at 1 microgram/ml relative to the two higher concentrations (20 and 100 micrograms/ml) for dogs treated with ammonium and sodium chloride, respectively. However, Vss of MTX at the targeted concentrations of 20 and 100 micrograms/ml was relatively constant. Plasma pH dependence of Vss was observed only at the plasma concentration of 1 microgram/ml, and on the average, ammonium chloride and sodium chloride treatments resulted in 50.0 and 31.3% higher Vss, respectively, when compared with the bicarbonate treatment. These phenomena appear to be adequately explained by the reported tissue uptake kinetics of MTX.
After entering the liver a drug molecule is removed by two competitive processes: (a) blood flow to carry it away intact from liver and (b) elimination by hepatic enzyme(s). The relative magnitude of the overall force or efficiency of these two processes will statistically decide its probability for elimination, i.e., extraction ratio (E). Blood flow rate is chosen to represent the force due to blood flow, and the force due to hepatic elimination can then be simply calculated in terms of blood flow per unit time. Under linear conditions any changes in either force can be used to predict new E. Binding in blood, permeability across hepatocellular membrane and intrinsic enzyme activity will affect the hepatic elimination force. The approach employed has virtually made no prior assumptions regarding distribution profiles of drug, enzymes, sinusoids and intracellular bindings as well as drug permeability. Bioavailability predictions upon changes in hepatic flow or protein binding are consistent with most reported data. It can explain potential differences in the fate of drug pre-equilibrated or not pre-equilibrated with blood before entering the liver and also that of metabolite performed or not performed in liver. Importance of erythrocytes as potential elimination barriers in hepatic first-pass effect and existence of both transverse and longitudinal (not considered in previous hepatic models) drug concentration gradients in the liver are emphasized. Applications to studies of instantaneous, time-averaged, beta and intrinsic clearances, as well as hepatic transit time and nonlinear kinetics are discussed. The present simple dynamic approach can also successfully predict the quantitative correlation between renal clearance and changes in urine flow and/or pH for many drugs in humans and animals. Using steady-state input conditions the present derived equations can be obtained thus adding the mathematical validity of the approach.
The whole blood from three human subjects, one dog and four rabbits was spiked with methotrexate (MTX) to yield appropriate concentrations, and was incubated at 37 degrees C and 50 oscillations per min. MTX was found to exhibit unusual distribution kinetics in whole blood; plasma MTX concentrations generally dropped to a minimum at about 5 min then increased and fluctuated somewhat irregularly afterwards. Differences of up to 21, 19 and 32% between maximum and minimum were found in the studies from human, dog and rabbit, respectively. These unusual distribution phenomena might be due to the Schiff base formation between free primary amino group(s) of MTX and free fatty aldehyde groups on blood cell membrane. Similar unusual distribution kinetics were observed with blood from three human subjects after kept at room temperature or in the refrigerator, and blood collected from three dogs after intravenous bolus or infusion of MTX. Formation of three metabolites including 7-hydroxymethotrexate was only found in blood from rabbits, but not from humans and dogs.
The pharmacokinetics of methotrexate and its metabolite, 7-hydroxymethotrexate (7-OH-MTX), were evaluated by a specific HPLC assay in patients receiving low dose (40 mg/m2) or high dose (750-1500 mg/m2) MTX. A wide range of total body clearance (1.03-5.13 ml/min/kg) was obtained in four subjects. The apparent renal clearances of MTX and 7-OH-MTX were found to decline with increasing serum levels, indicating the existence of saturable tubular secretion for the drug. The steady-state volume of distribution of MTX was 0.41-0.95 l/kg. Urinary excretion of MTX was almost complete at 36-48 h after dosing. The nonrenal excretion accounted for 17-39% of the dose. Extensive formation of 7-OH-MTX occurred at all dose levels, with their serum levels being 2.4- to 10-fold higher than MTX levels 24 h post infusion. The mean apparent renal clearance of 7-OH-MTX (0.08-0.13 ml/min/kg) was much smaller compared with that of MTX (0.63-2.62 ml/min/kg). The average saliva/serum level ratios were 0.009 and 0.078 in two patients studied.
A simple and sensitive high-performance liquid chromatographic assay was developed for the quantitative determination of major erythromycin components and their potential metabolites or degradation products in plasma and urine. An ether extract of alkalized plasma sample was chromatographed on a reversed-phase column and the components in the column effluent were monitored by an electrochemical detector. The recovery of the drug from extraction was virtually 100%. The detection limits for erythromycin A in plasma were 5-10 ng/ml and 30 ng/ml using 1 and 0.2 ml of sample, respectively. For urine samples, a simple one-step deproteinization with two volumes of acetonitrile was satisfactory for analysis. The method has been evaluated in plasma and urine from dogs receiving oral or intravenous erythromycin A. The standard curves for potential metabolites or degradation products were not constructed due to the lack of sufficient samples.