BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 3, 287-290 (1982)

BOOK REVIEWS

MICROSOMES, DRUG OXIDATIONS, AND CHEMICAL CARCINOGENESIS, Volumes I and 11, Minor J. Coon, Allan H. Conney, Ronald W. Estabrook, Harry V. Gelboin, James R. Gillette, and Peter J. O’Brien (Eds), Academic Press, New York, 1980.

These books are the proceedings of the Fourth International Symposium on Microsomes and Drug Oxidations held at Ann Arbor, Michigan in July 1979. A long series of papers on highly technical aspects of P-450 and related systems has been collected together to provide a summary of the state-of-the-art at the time in a field involving hundreds if not thousands of workers throughout the world, dominated by some of the leading investigators in biochemical pharmacology.

The books are divided into sections. In the first, chemical and physical character- ization of P-450 is considered in relation to source, techniques of preparation and a host of other variables. Then comes a series of papers on the mechanism of action of cytochrome P-450 and related enzymes in their various ro l e sd rug metabolism, steroid hydroxylation, carcinogenesis etc. Section I11 is concerned with the influence of membrane structure and protein synthesis on electron transfer components. Sections IV, V, VI, and VII review the metabolic fate of oxygenated compounds, microsomal enzymes and lipid metabolism, toxicity of foreign com- pounds as influenced by microsomal en- zyme activity, and finally, mutagenesis and carcinogenesis.

All in all, a timely and immensely valu- able compendium, dealing in welcome detail with a formidable array of informa- tion.

STEPHEN H. CURRY University of Florida

APPLIED BIOPHARMACEUTICS AND PHARMACOKINETICS, Leon Shargel and

Andrew B. C. Yu, Appleton-Century- Crofts, New York, 1980. CLINICAL PHARMACOKINETICS: Concepts and Applications, Malcolm Rowland and Thomas N. Tucker, Lea and Febiger, Philadelphia, 1980.

APPLIED PHARMACOKINETICS: Principles of Therapeutic Drug Monitoring, William E. Evans, Jerome J. Schentag, and William J. Jusko (Eds), Applied Therapeutics Inc., San Francisco, 1980.

DRUG ABSORPTION AND DISPOSITION: Sta- tistical Considerations, Kenneth S. Albert (Ed.), American Pharmaceutical Associ- ation, Washington D.C., 1980.

The later part of 1980, and the first few months of 1981 comprised a vintage period for publication of books in the field of pharmacokinetics. It is convenient to consider four of the publications of this period together. All four books are dated 1980, but they mostly appeared on the market in early 1981.

The book by Shargel and Yu is a paper- back and it fits a classical mould. In the late nineteen-sixties, courses arose in phar- macy schools under the general classifica- tion of ‘Biopharmaceutics’. These courses formalized existing classes concerned with drug absorption and excretion, introduced the concept of a biological subdivision of pharmaceutics, and dealt with the evalua- tion of dosage forms by means of bio- logical data. Additionally, detailed con- sideration of models in pharmacokinetics, sometimes mathematical models, some- times hydraulic models, and sometimes paper diagram models was added to the curriculum. The pharmacokinetics com- ponent gradually increased in complexity, so that in recent years many of these courses have consisted of much theoretical pharmacokinetics and only a small amount of biology.

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Shargel and Y u start their book with a mathematical introduction. This deals clearly with exponents, logarithms, differ- ential and integral calculus, and graphs. The latter section is particularly welcome, in an entire chapter of great value. It is surprising how little mathematical ability is really needed for pharmacokinetics, but a summary is nevertheless useful. The book continues with a chapter on rates and orders of reactions, and then moves into an introduction to pharmacokinetics, with particular consideration of transfer within, and of elimination from, one- compartment open models. The next chapter deals with two-compartment open models similarly. Bioavailability and ab- sorption come next, followed by clearance (both renal and hepatic), protein binding, intravenous infusion, and multiple dosing regimens. The next chapter is on non- linear pharmacokinetics.

Up to this point in this book the struc- ture has been presentation of models, fol- lowed by practice problems with solutions, then questions, which are problems for which the reader finds the answers in the back of the book. Many people will find this structure admirable. The clarity of presentation is magnificent and the material covered is correctly chosen. The problem is one inherent in the classical mould mentioned earlier. This book por- trays pharmacokinetics as an abstract theoretical subject, with examples only relevant to calculation examples, not im- mediately relevant to demonstration of the importance of the models.

In its later sections this book ‘goes clinical’, first in the area of dosage regi- mens, then in regard to children, the elder- ly, renal disease (in relation to which the nomographic methods of calculating dos- ing receive appropriate attention), and dialysis. There is no mention of hepatic disease or genetics. The final chapter is a brief theoretical consideration of relation- ships between effects and pharmacokinetic measurements. There are more examples in the clinical chapters than in others but they are still thin on the ground.

I found one or two reasons to disagree with the implications of certain diagrams, with some of the symbols used (especially

where symbols in diagrams and text are not consistent), and with some of the statements displaying acceptance of some of the unproved ‘truths’ of pharmacoki- netics, but with its virtues of a clearly defined objective (in the Preface), its systematic and logical approach, and its abundance of mathematical practice prob- lems, I think this book will serve that classical mould well.

At issue however, is whether the class- ical mould is the correct one. As Rowland and Tucker have observed with their own teaching: ‘Over the years the emphasis (has) shifted from kinetics and model(l)ing to providing a conceptual base for apply- ing pharmacokinetics to rational drug therapy’. In other words, pharmacoki- netics is increasingly important as a com- ponent of patient care, and, as far as undergraduate students are concerned, of decreasing importance as a theoretical exercise and in assessment of dosage forms.

Rowland and Tucker have organized their book in four sections. In the ‘Concepts’ section, attention is given to definition of terms, and to absorption, distribution and elimination mechanisms. Fundamental facts are carefully stressed. The value of clearance is considered. Simple equations are presented. The reader works from chapter to chapter building up his knowledge base using the simpler building blocks. This approach works smoothly, and involves links with the biological machine at the heart of the subject-the human body. The difference in this approach, compared with that of Shargel and Yu, is starkly obvious. In their second section, Rowland and Tucker con- sider ‘Disposition and Absorption Kine- tics’, stressing intravenous dose rate equa- tions, extravascular doses, and metabolite kinetics. The next section is on ‘Therapeu- tic Regimens’, stressing the techniques needed for construction of a dosing regi- men, and taking into account the relation- ship between effect and dose. Section IV then follows, concerned with ‘Individualization’. This section reviews the reasons for variability in drug res- ponse, including age and weight, renal

BOOK REVIEWS 289

function, drug interactions etc., with a chapter specifically concerned with monitoring drug therapy, and with em- phasis on those drug examples where monitoring has proved useful. The Ap- pendices to this book include sections on some of the standard mathematical tech- niques used in pharmacokinetics.

Certain characteristic features of the presentation of this book stand out. It is expensively produced, on high-gloss paper. Chapters start with a block of objectives, generously spaced out on a grey background. Some of the figures in- corporate colour. The figures are lhrge (and therefore clear, especially as they were obviously drawn by a skilled artist). There are plenty of examples at all points. There are many good calculation ex- amples. Against this, I found a few too many sweeping statements lacking suf- ficient basic evidence for their validity, some omissions, and 1 did not like some of the style, which too frequently instructs, as opposed to leads, the reader. I found too many phrases of the type: ‘let us look’, and ‘consider’ for my taste. Finally, this book is a little thin on bibliography. Neverthe- less, there can be no question of the impor- tance and future success of this text.

Evans, Shentag, and Jusko haveedited a compendium concerned only with prin- ciples of therapeutic drug monitoring. There are thirty-four contributors to the book, some with M.D.s, some with Ph.D.s and many with Pharm. D.s. The objective is provision of ‘an authoritative source of the objective criteria and systematic approaches necessary for rational applica- tion of pharmacokinetics in clinical prac- tice’. I am not sure what that statement means, but the past excessive considera- tion of mathematics at the expense of thoughts on patient care is rightly crit- icized. The book is concerned with those drugs which are commonly monitored by pharmacokinetic methods, provided they have a data base wide enough to warrant critical review. The emphasis is therefore on theophylline, aminoglycosides, cephalosporins, phenytoin, digoxin, and lidocaine, plus procainamide, quinidine, propranolol, salicylates, methotrexate, tri-

cyclic antidepressants, lithium, and heparin. The chapters on some of the groups (theophylline to lidocaine but not cephalosporins or digoxin) are character- ized by a primary chapter as an exposition of the monitoring principles, followed by one or more ‘counterpoint’ chapters. These counterpoint chapters are included where a consensus does not exist, to reflect positions of different investigators. This is an interesting use of the term. The golden age of counterpoint was a musical era when pairs or trios of melodies were inter- woven with the most glorious harmony ever devised. Is the analogy a good one I wonder?

The other chapters in this book deal with other aspects of monitoring. With consultation service systems, with the in- fluenceof various physiological variableson pharmacokinetics, and with guidelines for collection and analysis of data. A pleasant introductory chapter was provided by Dr. G. Levy.

This book will find application as a textbook for clinical pharmacology ex- periential courses, and it should be by the side of all clinical pharmacologists and pharmacy practitioners providing con- sultation services. Because it is so specific it will quickly go out-of-date. Because it was written by a consortium of authors it lacks consistent style, and reading it is not as straightforward as reading some other books. I recommend it for reference purposes.

Finally to the book edited by Albert. This does not live up to the promise of its title. It is a valua’ile summary of the standard practices relating to design of bioavailability experiments, FDA regula- tions relevant to them, and analysis of data from them. It has chapters on use of stable isotopes in bioavailability studies, and on disposition and absorption factors in bioavailability testing. These two topics are not strictly ‘statistical’, but they help form an interesting and useful book. The book does not however deal in any detail with the use of statistics in evaluating derived pharmacokinetics constants, and therein lies the disappointment.

STEPHEN H. CURRY University of Florida