Kenneth J. Himmelstein

A review of the applications of physiologically based pharmacokinetic modeling

The physiological pharmacokinetic approach to the modeling of drug distribution is reviewed. These models allow extrapolation outside the range of data with some confidence if the dominant mechanisms of transport are sufficiently well understood. In addition, it is possible to extrapolate to other species. Compartments correspond to anatomical spaces so that biochemical interactions (including drug effect or pharmacodynamics) can be incorporated in the model. The articles summarized in this review are limited to models dealing with drug application.

Prodrugs: A Chemical Approach to Targeted Drug Delivery

The term Prodrug is used to describe compounds which must undergo chemical transformation prior to exhibiting their pharmacologic or therapeutic action. The concept is not new since compounds such as acetylsalicylic acid (aspirin), as a prodrug of salicylic acid, and methenamine, as a prodrug of formaldehyde, were discovered in the late 19th century. The term “pro-drug or “pro-agent” was first used by Albert (1958) who suggested that this approach could be used to alter the properties of drugs, in a temporary manner, to increase their usefulness, and/or decrease associated toxicity.

Bleomycin pharmacokinetics in man. I. Intravenous administration.

SummaryDisposition of bleomycin was studied in plasma and urine (14 patients) and ascites fluid (2 patients) after intraperitoneal (IP) and intrapleural (IPl) administration, by radioimmunoassay. Peak plasma bleomycin concentrations after 60 U/m2 in 12 patients ranged between 0.4 and 5.0 mU/ml. For those patients with creatinine clearances greater than 50 ml/min the composite terminal phase bleomycin plasma half-lives (±SD) for three ‘IPl’ and six ‘IP’ patients were 3.4±0.3 and 5.3±0.4 h, respectively. The composite IP plasma half-life was significantly longer than the IPl hal-life (P<0.001) and previously reported IV half-life (t1/2=4.0 ±0.6 h) (P<0.01). In patients with normal renal function, bleomycin excretion during the first 24 h was in most cases lower following intracavitary (IC) than following IV administration (21.7%±8.6% vs. 44.8%±12.6%, respectively) (P<0.005). Comparison of bleomycin plasma concentration time products normalized for dose and half-life for IV and IC administration allowed an estimate that about 45% of the IC bleomycin dosage is absorbed into the systemic circulation. When calculating the total systemic exposure to bleomycin for a patient we suggest using the sum of the IV dose and one-half of the IC dose.SummaryBleomycin plasma decay kinetics and urinary excretion were studied in nine patients after IV bolus injections of 13.7 to 19.9 U/M2. Radio-immunoassay was used to measure bleomycin in plasma and urine samples. The resulting plasma concentration versus time data for each patient and the combined data obtained from all patients were fitted to a multiexponential equation using a nonlinear regression computer program. Pharmacokinetic parameters derived from the mean of all individual patient parameters and the composite of all plasma decay data were similar. Bleomycin initial and terminal plasma half-lives and volume of distribution for all plasma decay data from eight patients with normal serum creatinies were 24.4±4.0 min, 237.5±8.5 min, and 17.3±1.5 L/M2, respectively. Mean 24-h urinary excretion accounted for 44.8±12.6% of the dose in seven patients who had normal serum creatinine values and complete urine collections. The total body clearance and renal clearance in these seven patients averaged 50.5±4.1 ml/min/M2 and 23.0±1.9 ml/min/M2, respectively. One patient with a serum creatinine of 1.5 mg% (normal 0.7 to 1.3 mg%) who was given 15.6 U/M2 had a terminal plasma halflife of 624 min, a volume of distribution of 36.3 L/M2, and 24-h urinary excretion of 11.6% of the dose. We conclude that bleomycin after intravenous bolus injection has a relatively short terminal phase plasma halflife and relatively large urinary elimination.

Drug delivery from catalysed erodible polymeric matrices of poly(ortho ester)s.

The incorporation of small amounts of acid anhydrides into hydrophobic poly(ortho ester)s can facilitate the erosion and drug release from delivery systems. Since the reaction can be controlled by the amount of anhydride employed, the reaction is confined to a small reaction zone near the surface and constant delivery rates can be achieved. The catalytic activity is negatively correlated with the pKa of the corresponding acid of the anhydride.

A physiologically based pharmacokinetic model for the intraocular distribution of pilocarpine in rabbits

This report presents a mathematical model which has been developed to describe the intraocular disposition of pilocarpine following topical dosing in rabbits. The model uses experimentally determined parameters such as rates of tissue uptake of drug and equilibrium distribution coefficients. Differential mass balance equations for pilocarpine in the cornea, aqueous humor, irisciliary body, and lens were written and solved numerically. Measured tear concentrations, following topical dosing with pilocarpine, were fit by a monoexponential curve and used as the forcing function for the model. By using a combination of known physiological and experimentally determined parameters, predictions of intraocular tissue levels of pilocarpine were made. These predictions were then compared to experimentally determined concentration-time profiles.

Pharmacokinetics of 2-butanol and its metabolites in the rat.

A pharmacokinetic model is presented to describe the biotransformation of 2-butanol (2-OL) and its metabolites (2-butanone, 3-hydroxy-2-butanone, and 2,3-butanediol) using in vivo experimental blood concentrations. A flow limited model is developed to simulate 2-OL, 2-butanone (2-ONE), 3-hydroxy-2-butanone (3H-2B), and 2,3-butanediol (2,3-BD) blood concentrations in rats after oral administration of 2-OL. Assuming the only important site of 2-OL biotransformation is the liver, the tissues included are the liver and a volume of distribution, essentially body water in the case of 2-OL and its metabolites. A distribution coefficient is found to be necessary to describe the low concentration of 3H-2B in blood after administration of 2-OL. The need for this coefficient may be due to partitioning, binding, or altered transport rates from the liver. Inhibition of 2-ONE metabolism to 3H-2B by 2-OL has been included to explain a time delay in the appearance of 3H-2B after administration of 2-OL. Subsequent experimental verification confirms the mixed function oxidase inhibitory properties of 2-OL. The model is able to simulate blood concentrations and elimination of all four compounds after the oral administration of 2-OL. Additionally, the model also simulates the results obtained after i.v. administration of 3H-2B and 2,3-BD.

Mechanism of water transport in controlled porosity osmotic devices

Abstract Controlled drug delivery devices that release the drug from an osmotic core by a pumping mechanism are promising for the oral administration of water-soluble drugs. This study considers various possible paths for the transport of water through a porous cellulose acetate membrane which constitutes the outer wall of a particular osmotic device. It is shown that the mechanism of water transport is not solely by diffusion through the semipermeable cellulose acetate or water-filled voids: solute-excluding water-filled regions in the coat as well as the polymeric portion of the coat are important in water ingress into the osmotic pump.

Effect of an applied electric field on liquid crystalline membranes: control of permeability

Abstract This paper considers the development of liquid crystalline variable permeability membranes. The electrically induced changes in permeability of a liquid crystalline membrane composed of a 23% w/v solution of poly(γ-benzyl-l-glutamate) (PBLG) in dichloromethane are described. PBLG exists in the cholesteric mesophase in solution in a suitable α-helicogenic solvent. When an electric field is applied to a thin membrane comprised of this material, a transition to the nematic mesophase is triggered, and the permeability of the membrane for small organic permeants increases. This increase takes the form of a 50-60% increase in the steady state flux through the membrane.

Tissue distribution kinetics of tetraethylammonium ion in the rat

Tissue distribution kinetics of tetraethylammonium (TEA) ion in rats were studied following both constant-rate intravenous infusion and rapid intravenous injection of the drug. At a steady-state plasma concentration of 0.2 μg/ml, the tissue-to-plasma (T/P) concentration ratio of the kidneys, liver, heart, gut, and lungs exceeded 1,indicating that TEA is localized in these tissues. In vitrotissue homogenate binding and slice uptake experiments provided no evidence of TEA binding to tissue constituents, suggesting that the high T/P concentration gradient is due to an active transport process. The maximum concentration of TEA in all tissues occurred within 5–15 min after rapid injection of a 2-mg dose. Except for the liver, the subsequent decline of TEA concentration in various tissues over a 5-hr period was slow compared to that in plasma. Consequently, the T/P ratio of liver and kidney remained relatively constant, while those of the other tissues increased continually with time. These features of TEA tissue distribution kinetics can be predicted by a physiologically based pharmacokinetic model which incorporates both active and passive transport processes for the passage of TEA between blood and the tissue mass.

Some equilibrium and kinetic aspects of water sorption in poly(ortho ester)s

Abstract Poly(ortho ester)s are a class of erodible polymers suitable for the construction of drug delivery systems. Since the release of bioactive substances from these polymers depends on the hydrolytic cleavage of the backbone, the isothermal sorption and transport of water in various poly(ortho ester)s have been investigated. At 25°C and relative vapor pressure equal to unity, the amount of water sorbed at saturation ranges from 0.3% to 0.75% w/w. Application of a modified Henrys law to the data yields reasonable correlation. The diffusion coefficient of water in poly(ortho ester)s appears to be independent of film thickness, molecular weight and water activity. At experimental temperatures above the glass transition temperature of the polymers, a marked increase in water diffusivity was observed. The activation energies of the transport process are within the range usually found for synthetic polymers. These equilibrium and kinetic studies suggest that membranes made of copolymers tend to have a more open structure than single diol poly(ortho ester)s.