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Foreign Compound Metabolism in Mammals Volume 5
A Review of the Literature Published During 1976 and 1977
By D. E. Hathway
The Royal Society of ChemistryCopyright © 1979 The Chemical Society
All rights reserved.
BY P. G. WELLING
As in previous volumes, the prime objective of this chapter is to provide a selective review of the pharmacokinetic aspects of drug absorption, distribution, metabolism, and excretion. The required role played by pharmacokinetics during drug development, together with the continued search for the all too often well-concealed truth regarding the kinetics of drug disposition, continue to promote the expansion of the pharmacokinetic literature.
Many new and improved pharmacokinetic models ranging from novel simple concepts to those of bizarre complexity continue to appear. Paralleling these, and in fact far outstripping them in some cases however, is a proliferation of information regarding the practical, clinical aspects of pharmacokinetics. This aspect, which has gained its main impetus in pharmacy schools and teaching hospitals in the United States, represents one of the most viable areas of the science of pharmacokinetics.
The thrust toward clinical pharmacokinetics is reflected in the introduction of the new journal Clinical Pharmacokinetics, a long overdue medium which provides an outlet for informed reviews from drug experts on many aspects of practical application of pharmacokinetics in clinical practice. The effects of disease states on drug pharmacokinetics was the subject of a symposium at the 123rd annual meeting of the American Pharmaceutical Association. Ritschel has published the first handbook of basic pharmacokinetics which combines a concise presentation of instructional biopharmaceutics and pharmacokinetics with a useful, if rather short, table of drug pharmacokinetic constants. Two other useful books which have appeared during the review period are the second editions of 'Biopharmaceutics and Clinical Pharmacokinetics' and 'Drug Disposition and Pharmacokinetics'.
Theoretical papers which have appeared during the review period include an extensive discussion of 'well-stirred' and 'parallel-tube' models associated with hepatic drug clearance using lidocaine metabolism as a model system, model independent methods of estimating first-pass and extra-hepatic drug metabolism, the determination of rate constants, and also loading dose-drug infusion relationships in linear kinetic models and area–dose relationships in non-linear models. Other papers consider the estimation of pharmacokinetic constants using post infusion data, the use of dose–effect curves and biophasic drug levels in bioavailability calculations, the concept of distribution volume in pharmacokinetics and a transformation method for predicting plasma drug levels from dissolution rates. Galeazzi and Benet discuss some shortcomings in the Dost law of corresponding areas when calculating drug absorption rates in multi-compartment systems. Notari and Byron describe some parameter constraints when assuming 'flip-flop' characteristics for drugs obeying two-compartment kinetics, while Winne discusses deviations in drug absorption and membrane transport characteristics from the classical pH partition theory. Winne concludes that deviations by weak acids or bases from that theory may be due to several contributing factors including an unstirred surface layer, the distribution ratio of substance between the membrane barrier and bulk phase, a variable microclimate influenced by bulk phase pH, and also drug adsorption to the membrane surface.
Novel computer programs and analytical models have been described for optimum drug dosage calculation for obtaining initial estimates of polyexponential parameters and a comparison is presented of a new curve fitting program FUNFIT with an established program NONLIN. Colburn et al. discuss a new program based on NONLIN which estimates pharmacokinetic parameters from repetitive dose studies. The program is particularly useful in that it is sufficiently flexible to accommodate dose and dosing interval changes during a dosage regimen, and permits curve fitting based on a number of linear kinetic models.
Wagner describes a model to account for drug binding to proteins and tissues when estimating drug rate constants and clearances, and also comments on area calculations using Laplace transformations, and the implications of some multicompartment systems to their application in bioavailability estimations. The use of the curve-stripping program CSTRIP is described, particularly in terms of direct calculations of drug distribution volumes, clearances, and other parameters without deriving intra-compartment microsopic rate constants. Wagner also presents an argument concerning possible ambiguities in the interpretation of linear pharmacokinetic models. The problem is illustrated in Figure 1 in terms of 'irreversible' and 'reversible' drug transfer between input and disposition compartments. Wagner makes the point that although some exponential terms may disappear during curve stripping in the reversible input case, these alternative models introduce another degree of complexity and may lead to ambiguity in the selection of the correct pharmacokinetic model.
Drug Absorption and Bioavailability. — The bioequivalence of different drug products is of continuing concern and the recent rulings by the United States Food and Drug Administration have been summarized by Skelly. The summary defines such terms as bioavailability, pharmaceutical equivalence, pharmaceutical alternatives, bioequivalent drug products, and bioequivalence requirements. Skelly reiterates the opinion of the Food and Drug Administration that discriminating in vitro dissolution tests can be valid predictors of drug bioequivalence as well as a means of monitoring manufacturers' batch-to-batch uniformity. Others have discussed the analysis and interpretation of bioavailability studies in man and the importance of biopharmaceutics and pharmacokinetics in bioavailability assessment, characterization of new drugs, adjustment of dosing regimens, and the influence of disease states on drug disposition.
A symposium on Bioavailability and Clinical Pharmacokinetics, held at the fifth annual meeting of the American College of Clinical Pharmacology, included papers on biological availability and therapeutic equivalence, interpretation of bioavailability data, the industrial role in biopharmaceutics, and the application of pharmacokinetic data to clinical trials leading to IND/NDA submissions. The last paper considers classical bioavailability studies, and the application of these to clinical research, as the 'first' and 'second' mountains of drug disposition, and highlights some of the ways in which pharmacokinetic information may contribute to the optimization of drug therapy. The ability of pharmacists and physicians to interpret and evaluate bioavailability data was examined by Vinson and Schumacher, who showed that, although pharmacists generally scored significantly higher than physicians, neither group evaluated data as accurately as a panel of scientists.
The appropriate study designs and applications of bioavailability assessment under quasi- and non-steady-state conditions are described by Kwan and associates, while Smolen has reviewed the theoretical and computational basis for bioavailability determinations using pharmacological data. Particular reference is made to the two situations where the drug biophase is identified with or physically separated from the body plasma compartment. Although the use of pharmacological end-points provides an attractive alternative to chemical drug assays in bioavailability studies, the possibility of multiple and non-linear responses, the condition of the subject, and other factors which may contribute to biological variability, must be considered when interpreting the data.
Wagner has presented a modification of a previously described method of accelerated data convergence and its application to bioavailability assessment using area analysis. The two methods are basically similar, using equally spaced sequential data points to predict total area values based on an expression of the form of equation 1, where the Yi's represent areas at times 1, 2, 3, and at infinite
[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (1)
time. Greater accuracy was obtained with the modified method which used orthogonal least squares rat her than normal least squares analysis.
Topics concerning drug absorption which have been reviewed include the influence of splanchnic circulation on absorption, drug absorption in patients with gastrointestinal disease, and the influence of food and diet on drug absorption in normal individuals. In the last of these, drugs are classified into those in which absorption appears to be reduced, delayed, not affected, or increased by food; the first being by far the largest group. The author also points out the frequently ignored contribution of the size of accompanying fluid volumes to variations in circulating drug levels, and hence the possible therapeutic effect, of orally dosed drugs. Shenfield et al. have discussed drug absorption following direct dosage into the bronchi, with particular reference to the agents sodium cromoglycate, salbutamol, salmefamol, and rimiterol.
Drug Distribution and Elimination. — The influence of genetic and environmental factors on drug disposition in man has been reviewed by Vesell who, while emphasizing the importance of understanding the contribution of these factors, also indicates the extreme difficulty in measuring their relative influences at any specific time, other than in the basal state. The increasing interest and understanding of interactions affecting, and the clinical implications of drug binding to plasma and tissue proteins are reflected in the large number of reviews on this subject. Topics covered include drug binding to albumin and plasma protein, changes in the binding of drugs to plasma proteins in impaired renal and hepatic function, and the influence of albumin composition on drug binding. Differences in the binding of drugs to plasma proteins in the new-born and the adult are discussed by Kurz et al. The pharmacokinetic implications of changes in distribution volume, with particular reference to protein binding, have been described by Klotz. The combined effects of tissue and plasma protein binding of drugs on drug disposition and elimination have also been considered. The combined influences of tissue and plasma protein binding may affect circulating levels of free drug as described in equation 2, where CF is the concentration of circulating free
[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (3)
drug, AT is the total amount of drug in the body, VF is the distribution volume of free drug, 3 represents plasma volume, and γ and [member of] represent the ratio of the percentage of bound to unbound drug in serum and tissues, respectively. The way in which changes in binding may affect circulating levels of free drug is indicated in Figure 2. Changes in the binding of drug to tissues cause a linear change in free drug levels, while changes in binding to plasma proteins cause non-linear changes in free drug levels, with the greatest changes occurring for highly bound drugs with relatively small distribution volumes. The capacity of agents to cross the blood-brain barrier has been discussed in terms of capillary permeability coefficient. This method may be useful to study brain capillary permeability, associated with certain disease states. Yacobi and Levy compared serum protein-binding characteristics of weakly acidic drugs in normal and uraemic individuals, and also in rats. They concluded that correlations of drug-binding characteristics between drugs and subject groups were too poor for one drug to be considered as an index compound for other weakly acidic agents.
In the area of clinical pharmacokinetics, considerable attention has been paid to the treatment of patients with renal or hepatic insufficiency, and to the use of kinetic factors in clinical practice generally. Mechanistic papers describe renal tubular processing of drugs, drug distribution, and pharmacokinetics in renal disease and the interpretation of drug levels in uraemic individuals. Drug dosage in patients with compromised renal function has been considered in some detail. A review on this subject by Fabre and Balant discusses the effects of renal insufficiency on the disposition of 117 drugs. The principles of drug dialysis have been briefly reviewed. A new haemoperfusion column has been shown to have some advantages over conventional dialysers, and may be particularly useful for the removal of lipid-soluble compounds. The removal of drugs by conventional dialysers has been described for various antibiotics, anti-arrhythmic agents and cardiac glycosides, antihypertensive agents, analgesics, and sedative–hypnotic and anti-anxiety drugs.
The influence of liver disease on drug disposition is complicated by problems of methodology and interpretation; relevant parameters include the influence of altered hepatic blood flow, the efficacy of hepatic extraction and clearance, and polymorphism in drug acetylation. Renal failure may cause accumulation of active metabolites in the body, but may also be associated with inhibition of some intrinsic biotransformation steps including reduction, hydrolysis, and drug acetylation. Sessions at the 78th annual meeting of the American Society for Clinical Pharmacology and Therapeutics were devoted to aspects of drug absorption, distribution and excretion, and to pharmacokinetics.
Clinical Pharmacokinetics. — Most pharmacokinetic studies are conducted in 'healthy, young' volunteers to avoid variations due to disease and age. However, no such constraints apply to the drug recipient, and large deviations in drug kinetic behaviour occur. Morselli has shown profound differences in drug disposition in various age groups, with particular reference to neonates, while Rane and Wilson have described drug kinetics in infants and children. The inadequacy of pharmacokinetic and pharmacodynamic data for most drugs in children leads to empirically based therapy in many cases. Examples exist also of changes in drug kinetics in elderly patients. These may be due to diseased states, which are more prevalent in geriatric populations, reduced absorption, decreased metabolism, decreased binding of drugs to plasma proteins and other tissues, decreased kindey function, and poorer distribution into body tissues. Sex may give rise to differences in drug kinetics, but there is little information available on this phenomenon in man.
Krauer and Krauer have considered the problem of drug therapy during pregnancy, and advocate the use of computerized kinetic models to predict foetal drug exposure and to provide a guide for clinical use. Similarly, the influence of pregnancy on maternal drug kinetics is relevant. Circulating levels of Li, digoxin, and some anticonvulsant drugs fluctuate during pregnancy, and should be monitored. Other reviews consider drug kinetics in patients with cardiac failure, and also the theoretical and practical aspects of drug interactions in therapy.
Some aspects of the concepts and applications of pharmacokinetics in therapy have been described in a genera1, and in a particular setting. Schumacher has published an outline and reading list on this subject, and Scheiner et al. have described a data analysis technique which allows estimations of population characteristics of pharmacokinetic values using data obtained from care of patients. The method deals with fragmentary and unstructured data from separate individuals and with the generality allowed in pharmacokinetic model specification. This approach appears to have potential application in areas of retrospective data analysis. The program CSTRIP has been used to determine pharmacokinetic parameters for 20 drugs. The parameters include distribution volumes, clearances and t0.5 values, and the use of these in initiating therapy involving drug infusion or intermittent bolus i.v. therapy. A method for estimating clearance values for a particular patient, is described in detail. Other aspects of the computerized prescription of drugs have been reviewed by Mawer.
Excerpted from Foreign Compound Metabolism in Mammals Volume 5 by D. E. Hathway. Copyright © 1979 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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Table of Contents
ContentsChapter 1 Drug Kinetics By P. G. Welling, 1,
Chapter 2 Enzymic Mechanisms of Oxidation, Reduction, and Hydrolysis By P. Bentley and F. Oesch, 89,
Chapter 3 Enzymic Mechanisms of Conjugation By P. C. Hiram and P. Millburn, 132,
Chapter 4 Species, Strain, and Sex Differences in Metabolism By J. D. Baty, 159,
Chapter 5 Mechanisms of Chemical Carcinogenesis By D. E. Hathway, 190,
Chapter 6 Effect of Drugs on the Central Nervous system By B. E. Leonard, 244,
Chapter 7 Cardiovascular Drugs By C. Rhodes, 320,
Chapter 8 Sympathomimetic Agents and Bronchodilators By L. G. Dring and P. Millburn, 349,
Chapter 9 Anti-infective Agents By P. Johnson and J. D. Coombes, 369,
Chapter 10 Prostaglandins and Steroids I: Prostaglandins By G. R. Bourne, 387,
Chapter 11 Food Constituents By D. E. Hathway, 418,
Chapter 12 Agricultural Chemicals By C. T. Bedford, 436,
Chapter 13 Industrial Chemicals and Miscellaneous Organic Compounds By C. T. Bedford, 495,
Compound Index, 525,
Author Index, 538,