Journal of Pharmacokinetics and Pharmacodynamics, Vol. 28, No. 1, 2001

COMMENTARY The Rate and Extent of Oral Bioavailability versus the Rate and Extent of Oral Absorption: Clarification and Recommendation of Terminology Win L. Chiou1 Received August 3, 2000—Final September 25, 2000 In the literature, the meanings of the terms oral absorption and oral bioaûailability of drugs ûary greatly. Absorption has been considered to take place at the mucosal membrane of the gastrointestinal (GI) tract. It has also been defined as the process from the site of drug administration to the site of measurement. In the latter definition, the extent of oral absorption depends on the extent of first-pass elimination in the gut wall and liûer eûen though a drug may be completely absorbed from the GI tract. Moreoûer, these two terms haûe also been used interchangeably. Inconsistency in the definition of these two terms has led to ûarying interpretations of these terms among students, researchers and laymen, and such an inconsistency seems undesirable. Apparently because of these inconsistencies, improper correlations between the Caco-2 permeability or intestinal permeability and the oral bioaûailability of drugs subject to extensiûe first-pass effect may haûe occurred. It is suggested that absorption be defined as moûement of drug across the outer mucosal membranes of the GI tract, while bioaûailability be defined as aûailability of drug to the general circulation or site of pharmacological actions. Since transit times (this may range from about 1 min to seûeral hours) across enterocytes, liûer, lungs, and the peripheral ûenous sampling tissue are ûirtually unknown for all drugs, this factor alone would faûor the use of ‘‘oral bioaûailability rate’’ rather than ‘‘oral absorption rate’’ in all routine studies. KEY WORDS: oral absorption; oral bioavailability; first-pass accumulation; first-pass metabolism; absorption rate calculation; bioavailability rate calculation.

INTRODUCTION The terms oral absorption and oral bioavailability are often used in the pharmacokinetic and biopharmaceutic literature. These two terms have 1

Department of Pharmaceutics and Pharmacodynamics (M兾C 865), College of Pharmacy, The University of Illinois at Chicago, 833 South Wood, Chicago, Illinois 60613; e-mail: [email protected] 3 1567-567X兾01兾0200-0003$19.50兾0  2001 Plenum Publishing Corporation

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been treated either identically or differently in several widely cited books. Apparently because of this, confusion and inconsistent use of the terms have frequently occurred in publications and presentations. The purposes of this commentary are to briefly describe the terms absorption and bioavailability, to review their background, and to discuss some implications of interchangeability of the terms, as well as to recommend a uniform definition and use of these two terms for routine studies. From a physiological point of view, absorption can be regarded to take place at mucosal membranes of the gastrointestinal (GI) tract. Once drug molecules enter the membrane, they can be deemed absorbed from the GI lumen. The absorbed drug may be metabolized in epithelial cells (1) (i.e., the so-called first-pass gut wall metabolism) and the unmetabolized drug may be retained in epithelial cells (2–5) for various times, from a few seconds to probably up to several hours depending on the binding property and lipophilicity of drugs before being carried away by mesenteric blood to the liver (i.e., the so-called first-pass gut-wall transit time). The drug molecules entering the liver may be eliminated by metabolism and兾or biliary secretion (i.e., the so-called first-pass hepatic effect), and the uneliminated drug molecules may be retained in the liver for various times (6,7), from a few seconds to several hours, before being carried away by hepatic venous blood to the general circulation (i.e., the so-called hepatic first-pass transit time). The above notion of oral absorption taking place at the outer mucosal membranes of the GI tract is consistent with conventional studies of using intestinal and Caco-2 permeability or absorptive clearance of drugs to correlate with or predict the rate and extent of their oral absorption in humans (8–11). The above absorption concept has also been commonly used in the correlation between in ûitro dissolution rates and in ûiûo absorption (8). On the other hand, oral absorption has also been defined in a highly respected book (12) as the process by which unchanged drug molecules proceed from site of administration, i.e., mouth and兾or gut lumen, to the site of measurement within the body. The site of measurement is usually assumed to be the general blood circulation (12). In this definition, absorption is referred to as systemic absorption and incomplete dissolution or firstpass metabolism is considered as a cause of poor absorption (12). The above absorption concept is also consistent with the conventional one-compartment, multicompartment, or deconvolution theories described in some widely cited articles and books (13–17). Strictly speaking, in terms of the rate of drug absorption, the above site-of-administration-to-site-of-measurement absorption concept does not consider first-pass transit time across the gut wall and liver during absorption. Also, transit times across the lungs and the peripheral sampling tissue are ignored in the above defined process

Terminology for Oral Bioavailability and Absorption

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if peripheral venous blood is to be used for drug analysis (18). Since the site of measurement can also be urine, saliva, cerebral fluid, or other tissues, extension of the above absorption concept (12) to these sites obviously is not appropriate but may be theoretically acceptable according to such a definition. In an authoritative textbook (15), it has also been stated that ‘‘Bioavailability, in simple terms, refers to the rate and extent of drug absorption.’’ Thus, according to this definition, bioavailability and absorption may be used interchangeably and estimated using the same methods (15). On the other hand, bioavailability has also been frequently employed (19,20) to indicate intact drug molecules bioavailable to the general circulation or to the site of pharmacological or therapeutic actions such as heart tissue or brain. A term, absolute bioavailability, has also been commonly employed to indicate the fraction or percentage of dose bioavailable to the general blood circulation. In view of the above apparent inconsistency and confusion in the precise definition and meaning of absorption and bioavailability in widely used references, these two terms are often used by students (based on my own experiences at our University), researchers, and laymen to ‘‘unknowingly’’ mean either the same or different things depending on individuals. This is undesirable in our discipline. Furthermore, some researchers may not appropriately analyze or report their experimental data. For example, bioavailability data of drugs undergoing extensive first-pass effect may have been incorrectly used to correlate with permeability data obtained from Caco-2 or intestinal perfusion studies or with in ûitro partition coefficient data. In view of the above discussion, it is recommended that oral absorption be generally used to refer only to the movement of drug across the outer mucosal membranes of the GI tract, and oral bioavailability to the availability of drug at the normal site of measurement, i.e., general circulation, or the site of pharmacological兾therapeutic actions when being clearly referred to. The exact first-pass transit time from the mucosal membrane of the GI tract to the general circulation is virtually unknown for all drugs. Also, unless drugs are known to be not metabolized in the body (excluding gut lumen in this case), the exact extent of their first-pass elimination is also not known. Therefore, it appears more logical to use the term, the rate of oral bioavailablity (20) rather than the rate of oral absorption when the rate is calculated using conventional compartmental or noncompartmental methods (14–17). Also, the currently used in ûiûo absorption rate calculation methods such as the Loo–Riegelman method (14) may be renamed as bioavailability rate calculation methods.

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Finally, the issues raised above may have some regulatory implications. However, this is beyond the scope of the present Commentary. Readers are encouraged to express their views on any issues directly or indirectly related to this Commentary. REFERENCES 1. K. E. Thummel, K. L. Kunze, and D. D. Shen. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Ad. Drug Del. Reû. 27:99–127 (1997). 2. Y. S. Choi and W. L. Chiou. First-pass accumulation by drugs in gut wall after absorption: Mechanism and implication in absorption studies. Pharm. Res. 9:5–13 (1992). 3. Y. M. Choi, S. M. Chung, and W. L. Chiou. First-pass accumulation of salicylic acid in gut tissue after absorption in anesthetized rats. Pharm. Res. 12:1323–1327 (1995). 4. W. L. Chiou. We may not measure the correct wall permeability coefficients of drugs: Alternative absorptive clearance concept. J. Pharmacokin. Biopharm. 23:323–331 (1995). 5. M. A. Gibbs, M. T. Baillie, D. D. Shen, K. L. Kunze, and K. E. Thummel. Persistent inhibition of CYP3A4 by ketoconazole in modified Caco-2 cells. Pharm. Res. 17:299–305 (2000). 6. W. L. Chiou. Mean hepatic transit time in the determination of mean absorption time. J. Pharm. Sci. 72:1365–1368 (1983). 7. W. L. Chiou, S. M. Chung, and G. Robbie. Similarity or discrepancy in pharmacokinetic parameter between bolus and infusion studies. J. Pharmacokin. Biopharm. 25:471–476 (1997). 8. G. L. Amidon, H. Lennerna¨ s, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutical drug classification: the correlation of in ûitro product dissolution and in ûiûo bioavailability. Pharm. Res. 12:413–420 (1995). 9. P. Artursson and J. Karlsson. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun. 175:880–885 (1991). 10. U. Fagerholm, M. Johansson, and H. Lennerna¨ s. Comparison between permeability coefficients in rat and human jejunum. Pharm. Res. 13:1336–1342 (1996). 11. W. L. Chiou. The validation of the intestinal permeability approach to predict oral fraction of dose absorbed in humans and rats. Biopharm. Drug Dispos. 16:71–75 (1995). 12. M. Rowland and T. N. Tozer. Clinical Pharmacokinetics: Concepts and Applications, 3rd ed., Lea & Febiger, Philadelphia, PA, 1995, Section 1. 13. J. Wagner and E. Nelson, Perent absorbed time plots derived from blood level and or urinary excretion data. J. Pharm. Sci. 52:610–611 (1963). 14. J. Loo and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs. J. Pharm. Sci. 57:918–928 (1968). 15. M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982. 16. D. Cutler. Assessment of rate and extent of drug absorption. Pharmacol. Ther. 14:123– 160 (1981). 17. W. L. Chiou. New compartment—and model—independent method for rapid calculation of drug absorption rates. J. Pharm. Sci. 69:57–62 (1980). 18. W. L. Chiou. The phenomenon and rationale of marked dependency of drug concentration on blood sampling site: Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics. Part II. Clin. Pharmacokin. 17:275–290 (1989). 19. M. Rowland. Effect of some physiologic factors on bioavailability of oral dosage forms. In J. Swarbrick (ed.), Current Concepts in the Biopharmaceutical Sciences: Dosage Form Design and Bioaûailability, Lea & Febiger, Philadelphia, PA, 1973, chap. 6. 20. W. L. Chiou, S. M. Chung, and T. C. Wu. Apparent lack of effect of P-glycoprotein on the gastrointestinal absorption of a substrate, tacrolimus, in normal mice. Pharm. Res. 17:205–208 (2000).