Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Drug Bioavailability Studies John G. Wagner To cite this article: John G. Wagner (1977) Drug Bioavailability Studies, Hospital Practice, 12:1, 119-127, DOI: 10.1080/21548331.1977.11707065 To link to this article: http://dx.doi.org/10.1080/21548331.1977.11707065
Published online: 06 Jul 2016.
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Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Australian Catholic University]
Date: 11 August 2017, At: 07:54
Drug Bioavailability Studies IoH N
G . wAG NE R
University of Michigan
Downloaded by [Australian Catholic University] at 07:54 11 August 2017
All drugs are not created equal even if the pharmacopoeia seems to suggest they are. Factors that affect bioavailability among drugs of the same type (especially oral drugs) include not only disintegration and absorption rates but also the amount of food taken before or with the dose, interactions with other drugs, the physical state of the patient, and the "first-pass effect"upon drugs with high liver clearance.
Although this crucial subject is finally attracting widespread interest, it is still beset by misconceptions, so perhaps it is best to begin by defining the framework. First, the study of drug bioavailability seeks to answer two basic questions: What is the relative amount of an administered drug that reaches the general circulation and at what rate does this occur? For drugs given by bolus IV injection, the answers are wo% and instantaneously (or almost); but virtually all drugs require other routes of administration, and other routes fall short of this "ideal," especially the oral route. To determine just how short then becomes the task of bioavailability studies. Second, comparative bioavailability studies of dosage forms are concerned only with what goes on between the administration of the drug and its arrival in the bloodstream. What subsequently happens to the drug remains the concern of pharmacokinetics. Third, many people think that the study of bioavailability is synonymous with the study of the equivalence or inequivalence of generic drugs. This is not so. Bioavailability is a much broader subject, encompassing not only comParison of drug products containing the same active ingredients but made by different manufacturers but also several other important areas. These are the effects of food, age, or disease states on the absorption of drugs; the effect of one drug on the absorption of another; measurement of the "first-pass effect" on orally administered drugs; and the question of how the size of a dose or the route of administration may affect drug absorption in ways that modify drug toxicity. However, the study of drug bioavailability is Primarily concerned with the study of drug absorption, With particular emphasis on the absorption of oral drugs given as tablets or capsules. Since comparative bioavailability studies for establishing equivalence or inequivalence among generic drugs have attracted the most attention, let us begin there. In the late 196os highly sensitive and discriminating analytical techniques began to be applied to the study of equivalence, and
in 1971 I did a literature review covering some 12 commercially available generic drugs that had been studied for formulation differences. That review concluded that for 10 of the 12 groups of drugs studied there was evidence of significant brand differences in bioavailability. The 10 were acetylsalicylic acid, chloramphenicol, chlordiazepoxide, diphenylhydantoin, oxytetracycline, para-aminosalicylic acid, riboflavin, sulfisoxazole, tetracycline, and warfarin. Inequivalence had not been reported for the remaining two drugs, ephedrine and isoniazid, but the evidence concerning these was simply inconclusive. Hence, at that time the drug products of different manufacturers were equivalent for possibly only one or two of .the 12 drugs. Since 1971, of course, the list of generic drugs so studied has been growing steadily. By 1973, for example, a review sponsored by one manufacturer suggested that there was evidence of at least potential bioavailability problems for 73 generic drugs. In 11 others the evidence was indeterminate, while the absence of such problems was suggested or demonstrated for only three drugs as of that date. What was responsible for so many instances of inequivalence? While often the cause(s) remained obscure, many contributing factors were revealed by these studies. Often the problems did not arise from deficiencies or excesses of the active ingredients relative to the amounts stated on the products' labels, nor with any other aberration that would have been routinely weeded out by current compendia! standards. Rather, they had mostly to do with variations in the seemingly innocuous side of drugs: in the excipients used (binders, fillers, granulating agents, lubricants, disintegrants, dispersants, or coatings); in bulk (particle size, specific surface area, solubility, hydration, or crystallization); and in the salt or ester forms of the drug. It became
Dr. Wagner is Professor of Pharmacy, College of Phannacy, and Staff Member, Upjohn Center for Clinical Pharmacology, University of Michigan, Ann Arbor.
Hospital Pradicc Janu
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Drug Bioavailability Studies John G. Wagner To cite this article: John G. Wagner (1977) Drug Bioavailability Studies, Hospital Practice, 12:1, 119-127, DOI: 10.1080/21548331.1977.11707065 To link to this article: http://dx.doi.org/10.1080/21548331.1977.11707065
Published online: 06 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Australian Catholic University]
Date: 11 August 2017, At: 07:54
Drug Bioavailability Studies IoH N
G . wAG NE R
University of Michigan
Downloaded by [Australian Catholic University] at 07:54 11 August 2017
All drugs are not created equal even if the pharmacopoeia seems to suggest they are. Factors that affect bioavailability among drugs of the same type (especially oral drugs) include not only disintegration and absorption rates but also the amount of food taken before or with the dose, interactions with other drugs, the physical state of the patient, and the "first-pass effect"upon drugs with high liver clearance.
Although this crucial subject is finally attracting widespread interest, it is still beset by misconceptions, so perhaps it is best to begin by defining the framework. First, the study of drug bioavailability seeks to answer two basic questions: What is the relative amount of an administered drug that reaches the general circulation and at what rate does this occur? For drugs given by bolus IV injection, the answers are wo% and instantaneously (or almost); but virtually all drugs require other routes of administration, and other routes fall short of this "ideal," especially the oral route. To determine just how short then becomes the task of bioavailability studies. Second, comparative bioavailability studies of dosage forms are concerned only with what goes on between the administration of the drug and its arrival in the bloodstream. What subsequently happens to the drug remains the concern of pharmacokinetics. Third, many people think that the study of bioavailability is synonymous with the study of the equivalence or inequivalence of generic drugs. This is not so. Bioavailability is a much broader subject, encompassing not only comParison of drug products containing the same active ingredients but made by different manufacturers but also several other important areas. These are the effects of food, age, or disease states on the absorption of drugs; the effect of one drug on the absorption of another; measurement of the "first-pass effect" on orally administered drugs; and the question of how the size of a dose or the route of administration may affect drug absorption in ways that modify drug toxicity. However, the study of drug bioavailability is Primarily concerned with the study of drug absorption, With particular emphasis on the absorption of oral drugs given as tablets or capsules. Since comparative bioavailability studies for establishing equivalence or inequivalence among generic drugs have attracted the most attention, let us begin there. In the late 196os highly sensitive and discriminating analytical techniques began to be applied to the study of equivalence, and
in 1971 I did a literature review covering some 12 commercially available generic drugs that had been studied for formulation differences. That review concluded that for 10 of the 12 groups of drugs studied there was evidence of significant brand differences in bioavailability. The 10 were acetylsalicylic acid, chloramphenicol, chlordiazepoxide, diphenylhydantoin, oxytetracycline, para-aminosalicylic acid, riboflavin, sulfisoxazole, tetracycline, and warfarin. Inequivalence had not been reported for the remaining two drugs, ephedrine and isoniazid, but the evidence concerning these was simply inconclusive. Hence, at that time the drug products of different manufacturers were equivalent for possibly only one or two of .the 12 drugs. Since 1971, of course, the list of generic drugs so studied has been growing steadily. By 1973, for example, a review sponsored by one manufacturer suggested that there was evidence of at least potential bioavailability problems for 73 generic drugs. In 11 others the evidence was indeterminate, while the absence of such problems was suggested or demonstrated for only three drugs as of that date. What was responsible for so many instances of inequivalence? While often the cause(s) remained obscure, many contributing factors were revealed by these studies. Often the problems did not arise from deficiencies or excesses of the active ingredients relative to the amounts stated on the products' labels, nor with any other aberration that would have been routinely weeded out by current compendia! standards. Rather, they had mostly to do with variations in the seemingly innocuous side of drugs: in the excipients used (binders, fillers, granulating agents, lubricants, disintegrants, dispersants, or coatings); in bulk (particle size, specific surface area, solubility, hydration, or crystallization); and in the salt or ester forms of the drug. It became
Dr. Wagner is Professor of Pharmacy, College of Phannacy, and Staff Member, Upjohn Center for Clinical Pharmacology, University of Michigan, Ann Arbor.
Hospital Pradicc Janu
