Foreign Compound Metabolism in Mammals

Foreign Compound Metabolism in Mammals


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Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry.

Product Details

ISBN-13: 9780851860589
Publisher: Royal Society of Chemistry, The
Publication date: 12/31/1981
Series: Specialist Periodical Reports Series , #6
Pages: 405
Product dimensions: 5.43(w) x 8.50(h) x 1.06(d)

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Foreign Compound Metabolism in Mammals Volume 6

A Review of the Literature Published During 1978 and 1979

By D. E. Hathway

The Royal Society of Chemistry

Copyright © 1981 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-058-9


Drug Kinetics


1 Introduction

The review period 1978 — 1979 has witnessed a continued increase in the literature of many aspects of drug kinetics and, as in previous volumes, this chapter presents the literature concerning some of the major drug classifications. Stringent space restrictions require a selective rather than a comprehensive treatment, with emphasis being placed on fewer drug groups and those communications which, in the reviewer's opinion, reflect the more important contributions in particular areas.

The increasing awareness of the importance of factors influencing drug absorption and disposition is reflected in the introduction of two new journals, Biopharmaceutics and Drug Disposition and Pharmacy International, while a new journal concerned with nutrient-drug intcractions will appear shortly. New books have been published on the pharmacokinetics of chemotherapeutic agents, principles and perspectives in drug bioavailability, drug fate and metabolism, and the fate of drugs in the elderly. A useful text on basic pharmacokinetic principles has been introduced by Niazi.

Theoretical papers published during the review period include discussions on the time-dependency of the induction of drug metabolism, the use of statistical moments in pharmacokineticanalysis, and the fitting of kinetic data to biexponential functions. This last publication compares the use of expressions of a form of equation 1

C = Ae-αt + Be-βt (1)

and also the differential and integrated forms of equation 2


for the non-linear computer analysis of biexponential data. In equation 1, A, B, α, and β are model independent hybrid constants, while in equation 2 the k's are first-order rate constants, and Xp and Ic are model-related parameters. The authors show that while computer convergence is slower with the differential form of equation 2 than with the integrated form, the accuracy and precision obtained from equations 1 and 2 are similar. They point out, however, that the use of either the differential or the integrated form of equation 2 is necessary to obtain the variance of the least-squares estimate of the particular k values.

Problems associated with drug accumulation in the body during continuous or repetitive doses continue to attract attention, and methods are described to predict accumulation profiles for drugs obeying Michaelis–Menten kinetics following zero-order, first-order, and instantaneous absorption, and also for drugs with nonlinear protein and tissue binding characteristics. Estimates of kinetic parameters for drugs exhibiting linear kinetics, based on two data points obtained at steady-state, are described by Bjornsson and Shand. The method, which is based on simple algebraic functions, is more reliable for drugs obeying one-compartment kinetics than for those with more complex kinetic profiles. A previously described method for rapid attainment of steady-state drug levels using a two-step infusion has been expanded by Zimmerman, who also describes the contribution of error effects in the prediction of steady-state values for drugs with biexponential drug profiles. Similar error effects have been described in predicting drug and metabolite urinary excretion profiles by the accelerated convergence technique for drugs which obey biexponential kinetics.

Applications of numerical deconvolution and linear systems analysis have been described for the calculation of in vivo drug dissolution, absorption, and metabolism, and also pharmacological data. Although theoretically sound, these approaches may suffer from the common problem of function identity and also data noise.

Other communications, of perhaps more practical application, have considered the dependence of pharmacokinetic parameters on body weight, and theoretical aspects of drug monitoring in serum and saliva. The use of general pharmacokinetic principles in drug therapy is advocated by Boëthius and Sjöqvist. These authors comment on the considerable variation in drug dosage, particularly of antidepressants and β-receptor blocking agents, and the poor correlations in some cases between dose adjustment and patient condition. A series of articles on the use of pharmacokinetics in drug therapy has been published by Schumacher et al. A method of individualization of drug dosage, with particular reference to chloramphenicol and theophylline, has been described by Koup et al. This method, which is based on a single drug-level determination, is as accurate as traditional pharmacokinetic methods requiring more extensive drug-level data. Supporting evidence for an earlier contention, that the use of one-compartment model kinetics may introduce error into the calculation of drug clearance values for drugs which obey more complex models, is presented by Dvorchik and Vesell. From previously published data, these authors show that the calculated error varied from 1% in the case of phenobarbital, to 81% in the case of cephalexin, and 196% in the case of ampicillin.

Two authors have commented on the errors involved in the use of the trapezoidal rule for determining areas under drug plasma concentration time curves. It is recommended that incorrect area estimates may be avoided if a linear trapezoidal method of the form of equation 3 is employed for pre-peak and plateau data in absorption studies, while a logarithmic trapezoidal method of the form of equation 4 is used for post-peak data:



The latter equation, in which Ci is concentration at time ti, applies for all exponentially declining drug profiles.

Recent advances in the use of physiologically based pharmacokinetic models, with particular reference to thiopental cytarabine, actinomycin D, sulphobromophthalein, salicylate, lidocaine, adriamycin, digoxin, methotrexate, and cephalosporins are reviewed by Himmelstein and Lutz. While describing the advantages of the physiological approach, these authors also appreciate the shortcomings. Model verification is difficult and generally has to be done in experimental animals. Each anatomical compartment represents a constant in the model, and failure to predict drug levels in any tissue will necessarily invalidate the model. The distribution of drug between various tissues in physiological models is in many cases a function of the intrinsic drug distribution characteristics and route of administration.

Drug Absorption and Bioavai1ability. — Reviews and communications have been published on the influence of formulation factors, intestinal mocroflora, and blood flow on the rate and extent of drug absorption. In summarizing his own data and also those from other laboratories, Melander confirms the unpredictable and capricious nature of the effect of food-–drug interactions on drug availability. While food has been shown to enhance the absorption of propranolol, metoprolol, hydralazine, and nitrofurantoin, it reduces the absorption of isoniazid, rifampicin, tetracycline, ampicillin, and other drugs.

In addition to events which occur within the lumen of the gastrointestinal (GI) tract, drug availability is influenced also by gut-wall metabolism, hepatic elimination, hepatic blood-flow, and enterohepatic cycling. A combined perfusion/compartment model is proposed by Colburn to separate these factors. The model, illustrated in Figure 1, permits derivation of equations to estimate the pre-absorptive, epithelial, and hepatic first-pass metabolism, and also to establish limits for the true absorption rate constant. The availability of a drug which is subject to enterohepatic circulation may be increased in cases of impaired bile flow while the availability of a drug subject to first-pass metabolism may be improved in cases of increased splanchnic blood flow. The latter has been demonstrated by the use of the simple perfusion model illustrated in Figure 2. Increased values of Q for finite time periods, as occurs when a drug is taken after a meal, may cause a marked increase in circulating drug levels (Figure 3). This evidence may provide a mechanism to explain increased levels of some circulating compounds in non-fasted individuals that were previously reported.

Although the use of a parenteral dose of a drug as a reference standard is the ideal procedure, when measuring the bioavailability of an oral dosage form, further evidence has validated a renal clearance perturbation method, which may provide accurate drug availability estimates in thz absence of parenteral data. The method is limited to drugs, the clearance of which can be varied experimentally without changing drug distribution characteristics. The use of pharmacokinetic and pharmacodynamic data in measuring drug bioavailability, and the influence of migraine on drug absorption, have been reviewed.

While pulmonary compared with enteral absorption of drugs is rapid the rate of absorption of different compounds varies widely depending on the physicochemical properties of the compounds and on whether transport is active or passive. Quantitative analysis of animal data suggests that pulmonary epithelium contains at least three different populations of pore size, each presumably allowing passage of molecules below a certain size, in relation to their diffusion coefficients, while restricting passage of larger molecules. While most compounds penetrate the pulmonary epithelium by passive diffusion, some organic anions are transported both by passive diffusion and by specific transport processes, which are saturable. In addition to absorption processes, the lungs also play a major role in drug metabolism and excretion. Consideration of pulmonary blood flow and induction of drug metabolizing enzymes suggest that the lungs play a role in the total body clearance of some drugs, which has been poorly recognized hitherto.

Drug Distribution. — Drug distribution is a complex function of the route and rate of absorption, relative blood flow to various organs, the partition coefficient of drug between the blood and other tissues, and also of tissue and plasma protein binding. The clinical significance of the protein binding of drugs has been reviewed by Buchanan, while the influence of disease states, in particular hypoalbuminaemia, on drug-binding characteristics has been discussed by Tillement et al. Dextran-induced hypoalbuminaemia has been proposed as a model for the investigation of the influence of protein binding on drug pharmacokinetics. Dextran appears to cause a decrease in the plasma albumin with only a slight change in total protein. The binding and distribution characteristics of a drug will markedly affect the drug biological t0.5, and also its dialysing characteristics.

The apparent overall distribution volume of a drug, V, may be approximated by equation 5


where Vp and Vt are the plasma and tissue volumes, and fp and ft are the free fractions in plasma and tissue respectively. This expression, which may be derived from pharmacokinetic or .distributional principles, may be useful in relating the possible effect of disease or other factors to extravascular drug binding.

Novel methods have been described to calculate the distribution volume of drugs obeying first-order, and Michaelis–Menten elimination kinetics. The second of these methods involvcs the use of simultaneous bolus injection and infusion, and numerical integration of a cubic expression to obtain an estimate of the distribution volume. Although the method assumes one-compartment model kinetics, it may be used also to obtain the overall distribution volume for drugs which obey multi-compartment kinetics. Others have described the periodicity of the distribution phase of i.v. dosed drugs, and the relationship between drug disposition and pharmacological effect.

Drug Metabolism and Excretion. — Considerable attention has focused on factors influencing drug metabolism. Drug biotransformation may be altered by exposure to chlorinated insecticides, and other halogenated hydrocarbons, tobacco smoking, and malnutrition. Hepatic biotransformation and first-pass hepatic clearance may be reduced in hepatic disease. However, much of the available data on these subjects is conflicting. Hepatic blood flow in adult man is ca. l00ml min-1 for each lOOg of liver mass, of which 70 — 75% is supplied by the portal vein. Hepatic blood flow may be significantly reduced in liver disease, and correlations based on an 'intact hepatocyte hypothesis' have been drawn between the extent of liver disease and hepatic blood flow or extrahepatic shunting. In moderate, chronic liver disease the hepatic blood flow may be decreased by approximately l6%, while in severe chronic disease, it may be reduced by 50%, accompanied by extensive extrahepatic shunting. There are considerable individual differences in the rate and extent of metabolism of some drugs and also in the degree of enzyme induction. Models have been developed to simulate hepatic organic anion metabolism, with particular reference to sulphobromophthalein, and also to estimate systemic availability of orally dosed drugs, which are subject to pre-systemic metabolism.

Pang et al. have discussed possible errors in the estimation of Michaelis-Menten constants associated with hepatic drug metabolizing systems. On account of the inaccessibility of sampling sites, and the complex variables influencing the rate of metabolism, considerable error may be introduced into the estimation of the Michaelis–Menten constant Km. The potential error in calculating this parameter is greater for drugs with high hepatic extraction ratios than for drugs with lower extraction ratios. Biliary excretion of drugs in man, and the relationship between biliary excretion and enterohepatic circulation, have been reviewed. Renal failure may cause not only impaired renal excretion but also changes in drug metabolism and protein binding leading to alterations in drug pharmacokinetics. Altered renal haemodynamics may induce fluid retention with consequent changes in drug-distribution volume. Apart from acute and chronic renal failure, renal perfusion may be reduced below normal in states of congestive heart failure and in liver disorders such as cirrhosis. Accurate assessment of renal function is important for a safe and effective dosage of compounds, which are cleared wholly or partially through the kidneys, and procedures useful in designing individualized dosage regimens have been described. These procedures take into account saturable renal tubular secretion and reabsorption in the presence of constant glomerular filtration. Drug kinetics in renal failure may be predicted using '1-point' or 'repeated 1-point' procedure. The latter method, which allows for changes in drug distribution characteristics in renal impairment, is based on the determination of a single drug level at the same time within two or more consecutive dosage intervals. The drug-elimination rate constant is then predicted by equation 6


where C1 and C2 are drug levels during dosage intervals τ1 and τ2 respectively.

Unlike creatinine clearance, which provides an immediate and absolute measure of renal function, serum creatinine is subject to other variables such as weight, age, and muscle activity. A nomogram relating serum creatinine and creatinine clearance that takes other parameters into account is described by Bjornsson.

The influence of a patient's condition on drug kinetics is the subject of increasing interest. Reviews and commentaries discuss drug dosage in paediatric. and geriatric patients, and also the pharmacokinetics of drugs in patients with pulmonary disease, and in conditions of trauma and surgery.

Elimination of unwanted drugs from the body may be expedited by haemoperfusion. This method, which has some advantages over dialysis, has the same basic limitation in being less efficient for drugs with large distribution volumes and high intrinsic clearances than for drugs with small distribution volumes and low intrinsic clearances.

2 Drugs Acting on the Central Nervous System

Psychotherapeutic Agents. — Despite the increasing practice of monitoring circulating levels of psychotropic drugs in patients, there is little evidence to indicate a reliable relationship between circulating drug levels and therapeutic effect. At a Ciba Foundation Symposium in July 1979 it was concluded that, while there is some evidence for a therapeutic range within which optimal response is obtained, the value of monitoring the drugs is doubtful. Some of the problems associated with pharmacokinetic interactions of psychotropic drugs are discussed by Kaumeier.


Excerpted from Foreign Compound Metabolism in Mammals Volume 6 by D. E. Hathway. Copyright © 1981 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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Table of Contents


Chapter 1 Drug Kinetics By P. G. Welling,
Chapter 2 Enzymic Mechanisms of Oxidation, Reduction, and Hydrolysis By P. Bentley and F. Oesch, 64,
Chapter 3 Enzymic Mechanisms of Conjugation By P. C. Hirom snd P. Millburn, 111,
Chapter 4 Species, Strain, and Sex Differences in Metabolism By J. D. Baty, 133,
Chapter 5 Mechanisms of Chemical Carcinogenesis By D. E. Hathway, 160,
Chapter 6 Drugs Acting on the Central Nervous System By C. Rhodes, 198,
Chapter 7 Cardiovascular Drugs By G. R. Bourne, 231,
Chapter 8 Biotransformation of Sympathomimetic Agents and Bronchodilators By L. G. Dring and P. Millburn, 247,
Chapter 9 Anti-infective Agents By P. Johnson and J. Skidmore, 261,
Chapter 10 Steroids and Antihormones By G. H. Thomas, 278,
Chapter 11 Food Additives By S. Gangolli, 291,
Chapter 12 Agricultural Chemicals By C. T. Bedford and C. J. Logan, 301,
Chapter 13 Industrial Chemicals and Miscellaneous Organic Compounds By C. T. Bedford and I. J. G. Climie, 330,
Chapter 14 Cancer Chemotherapeutic Agents By G. F. Kolar, 357,
Index of Compounds and Metabolites, 377,

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