Clearance studies of methotrexate in dogs after multiple-rate infusion.

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.

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.

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.

Pharmacokinetics of creatinine in man and its implications in the monitoring of renal function and in dosage regimen modifications in patients with renal insufficiency.

A single-compartment model is proposed to describe the pharmacokinetics of creatinine in man. Based on the information from the literature, it was estimated that the average biological half-life of creatinine in normal male adults between 20 to 39 years old is 3.85 hours. This half-life is prolonged in renal patients and becomes 77 hours when renal function decreases to 5 per cent of normal. Based on pharmacokinetic analysis, it was also shown that the time required to reach a new steady-state serum creatinine level after onset of renal failure is highly dependent upon the degree of renal insufficiency. For example, for the subjects analyzed in this paper, it was estimated that it will take 1.1, 2.5, 6.7, and 13.4 days to reach 95 per cent of the steady-state levels when the renal function drops to 50, 25, 10, and 5 per cent of the normal capacity. The model analysis also predicts that from a practical point of view the daily fluctuation in serum level in patients with better than 25 per cent of normal renal function is not very significant. On the other hand, the fluctuation in the early stage of severe renal failure is predicted to be very dramatic. The analysis also predicts that the serum level will decrease to a normal or near normal value within two days after improvement of renal function from moderately to severely impaired state. The data obtained from an anuric patient seems to support the validity of the pharmacokinetic approach used in this study. The implications of the above pharmacokinetic analyses for the monitoring of renal function and dosage regimen modifications in patients with renal insufficiency were discussed.

Rapid estimation of volume of distribution after a short intravenous infusion and its application to dosing adjustments.

A simple and a rapid method to estimate the apparent volume of distribution of drug after single or during multiple short-term intravenous infusion is proposed. This is based on the back extrapolation to the midpoint of infusion. An equation simpler than one previously reported in the literature is also derived to calculate the maintenance dose for multiple short-term intravenous infusion. In addition, an equation to estimate the "priming dose" for infusion during multiple infusion regimen is also derived. The derivations of the equations are based on a linear one-compartment open model for drug disposition in patients. The prposed method is thought to be adequate for the purpose of rapid individualization of dosage regimens. The simplicity of the method, in particular, the solution by the graphic method for estimation of the apparent volume of distribution, might be specially useful for clinicians not well versed in mathematics in applying clinical pharmacokinetics to drug therapy.

Pharmaceutical applications of solid dispersion systems: X-ray diffraction and aqueous solubility studies on griseofulvin-polyethylene glycol 6000 systems.

The X-ray diffraction method was used to characterize physiochemical properties of griseofulvin dispersed in polyethylene glycol 4000 and 6000. Results indicate a negligible or very limited solid solubility of griseofulvin in the pulverized solid dispersions. Pulverization and aging had pronounced effects on the X-ray diffraction spectrum. Results from aqueous solubility studies of griseofulvin in various concentrations of polyethylene glycol 6000 further indicate weak or insignificant interactions between the drug and the carrier. Mechanisms are postulated to account for the reported marked enhancement of dissolution rates and oral adsorption of griseofulvin dispersed in these carriers.

New calculation method of mean total body clearance of drugs and its application to dosage regimens.

A new method for calculating the mean total body drug clearance is proposed for determining the mean dosing rate for patients. In this method, the mean clearance can be calculated from the individual clearance values by the harmonic mean method, or it can be determined by dividing the same absorbed dose by the arithmetic mean of the areas under the plasma level-time curve from time zero to infinity from all of the subjects or patients studied. In this method, the arithmetic mean method is assumed to have been used for calculation of literature mean plasma levels. Various methods for calculating mean clearances also are evaluated. These methods yield different mean clearance values from the same set of individual data, resulting in different dosage regimen recommendations.

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.

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.

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.

Fluorocarbon aerosol propellants VIII: solubility of trichloromonofluoromethane in dog blood and tissue homogenates.

The solubility of trichloromonofluoromethane in dog blood and tissue homogenates was measured indirectly using the head-space method at 37 degrees. These values, except that in dog blood, were used to estimate the solubility in the whole tissues or organs. In most cases, the solubility so obtained was independent of equilibrium concentration. However, a considerable concentration dependence for the solubility was observed in dog heart and kidney. The highest solubility found was in dog fat versus air, i.e., 45.6, which is almost 220 times higher than the solubility in water or normal saline. Fat solubilization and specific binding interactions appeared to be the two major factors in determining the solubility. The pharmacokinetic implications of such findings are discussed.

Fluorocarbon aerosol propellants IX: adsorption on activated charcoal.

The adsorption of three commonly used fluorocarbons, trichloromonofluoromethane, dichlorodifluoromethane, and dichlorotetrafluoroethane, on activated charcoal was studied at 25 degrees. The adsorption versus pressure plots are consistent with the Brunauer, Emmett, and Teller (BET) type II and type IV isotherms, which can be explained as the condensation of the gaseous molecules in a wide range of pores in the activated charcoal. The monolayer capacity derived from the BET equation is discussed and used to estimate the volume of micropores present in the activated charcoal. Below the relative pressure of 0.01, the adsorption deviated from the BET plot. The deviation revealed that the adsorption capacity and adsorption potential at these lower pressures are greater than the extrapolated values. It is concluded that activated charcoal can be used effectively to remove propellants from the air in pollution control.

Fluorocarbon aerosol propellants X: pharmacokinetics of dichlorotetrafluoroethane in dogs.

An intravenous dosage form of dichlorotetrafluoroethane, a common fluorocarbon aerosol propellant, was formulated in polyethylene glycol 400 for single dosing to unanesthetized dogs. A three-compartment open model was proposed for the disposition of this compound in dogs, with average half-lives of 1.3, 9.6, and 50.8 min for the three disposition phases. An analysis of tissue compartment distribution following a single dose showed that it took about 2 hr to achieve pseudo-distribution equilibration, following which more than 90% of the propellant remaining in the body was retained in the tissue compartments. Pulmonary clearance and volumes of distribution were calculated considering the first-pass effect through the lungs. The volume of distribution was approximately 10 times the body weight in terms of blood concentration, and about 84% of the propellant was cleared from the blood passing through the lungs in each cycle.

Pharmaceutical applications of solid dispersion systems: dissolution of griseofulvin-succinic acid eutectic mixture.

The dissolution profile of the griseofulvin-succinic acid eutectic mixture system was evaluated using the powder and constant-surface are tablet methods. Factors contributing to the enhancement of griseofulvin dissolution from the dispersion in succinic acid are discussed. Contrary to the original proposal of Sekiguchi and coworkers, dissolution rates of driseofulvin from solid dispersions were found to be markedly affected by the particle size of solid dispersions.

Fluorocarbon aerosol propellants XI: Pharmacokinetics of dichlorodifluoromethane in dogs following single and multiple dosing.

A three-compartment open model was proposed for the disposition of dichlorodifluoromethane in dogs with average half-lives of 1.47, 7.95, and 58.5 min for the three disposition phases. This proposal is contrary to several studies that monitored blood levels for a shorter period. An analysis of the tissue compartment distribution following a single dose showed that about 1.5 hr was required to achieve pseudodistribution equilibration, following which more than 90% of the dose remaining in the body was retained in the tissue compartments. The pulmonary clearance and volumes of distribution were calculated considering the first-pass effect through the lungs. The volume of distribution after reaching pseudodistribution equilibrium was approximately 10 times the body weight in terms of the blood concentration, and about 68% of the propellant was cleared from the blood passing through the lungs in each cycle. Disposition of the propellant followed dose-independent kinetics after multiple dosing. No volatile metabolites were detected in the blood using GC.

Fluorocarbon aerosol propellants. VI: Interspecies differences in solubilities in blood and plasma and their possible implications in toxicity studies.

Solubilities of the three most commonly used fluorocarbon aerosol propellants were determined in the blood and plasma of humans, monkeys, dogs, rats, and mice. Differences as large as approximately fourfold in blood and more than 33-fold in plasma were found in different species. The partitioning of fluorocarbons between blood cells and plasma showed even greater differences between species. An indirect method was suggested for the calculation of plasma concentrations from total blood concentrations. A comparative evaluation was reported for the nonprotein bound fractions of fluorocarbons in the blood samples of various species. A correlation was drawn for the pharmacokinetic properties of the fluorocarbons within and between species, and a rationale was provided for the extrapolation of toxicity data from animals to humans.

Fluorocarbon aerosol propellants V: binding interaction with human albumin.

Binding of trichloromonofluoromethane, dichlorodifluoromethane, and dichlorotetrafluoroethane was studied in aqueous 5% human albumin solution, using the partition coefficient method in sealed serum bottles. The partition coefficient and the fraction of fluorocarbons bound were highly dependent on fluorocarbon concentrations. The average binding sites per molecule of albumin were 2.17, 0.30, and 0.42 and the binding association constants were 1.11 X10-3, 1.73 X10-3, and 5.06X10-3 M-minus 1, respectively. At the lowest concentration studied, 62.3, 25.5, and 65.6% were found bound to albumin, respectively. This appears to represent the first extensive study on any gas-albumin interaction.

Fluorocarbon aerosol propellants IV: pharmacokinetics of trichloromonofluoromethane following single and multiple dosing in dogs.

An intravenous dosage form of trichloromonofluoromethane, a common aerosol propellant, was formulated in polyethylene glycol 400 for single and multiple dosing to unanesthetized dogs. A three-compartment open model was proposed for disposition of this compound in dogs with average half-lives of 3.2, 16, and 93 min for three disposition phases. This finding is contrary to several reports where blood levels were monitored for shorter periods. A computer analysis of tissue compartment distribution following a single dose showed that about 2 hr was required to achieve pseudodistribution equilibration, following which more than 90% of the dose remaining in the body was retained in tissue compartments. Pulmonary clearance and volumes of distribution were calculated considering first-pass effect through the lung. The volume of distribution was approximately six times the body weight in terms of blood concentrations, and about 30% of the propellant was cleared from blood passing through the lung in each cycle. Disposition of propellant followed dose-independent kinetics after multiple dosing, and accumulation in tissues continued for a much longer period, resulting in high tissue compartment levels.

Enhancement of dissolution rates of poorly water-soluble drugs by crystallization in aqueous surfactant solutions I: Sulfathiazole, prednisone, and chloramphenicol.

Effects of crystallization of poorly water-soluble drugs in aqueous surfactant solution on in vitro dissolution rates were investigated. Marked enhancement was observed for chloramphenicol, sulfathiazole, and prednisone. Differential thermal analysis studies indicated the presence of small amounts of surfactant in surfactant-treated crystals. Possible mechanisms of dissolution enhancement are discussed.

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.