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Drug buffer solutions were placed into the GIT of an in situ rat preparation. The apparent first-order absorption rate constants are based upon drug disappearance from the buffer solution.

Drug buffer solutions were placed into the GIT of an in situ rat preparation. The apparent first-order absorption rate constants are based upon drug disappearance from the buffer solution.

1/time). More rapid absorption rate is indicated by a numerically larger rate constant. There are three important comparisons that should be made in examining these data:

1. By comparing gastric absorption at pH 3 and pH 6, where surface area and factors other than pH are constant, one sees that the general principle is supported; acid drugs are more rapidly absorbed from acidic solution, whereas basic drugs are more rapidly absorbed from relatively alkaline solution.

2. At the same pH (i.e., pH 6), acidic and basic drugs are more rapidly absorbed from the intestine than from the stomach, by virtue of the larger intestinal surface area.

3. Acidic drugs are more rapidly absorbed from the intestine (pH 6), although there is substantial ionization, compared with the rate of gastric absorption, even at a pH where the drug is in a far more acidic solution (pH 3). Again, this is primarily a result of surface area differences.

The pH-partition hypothesis provides a useful guide in predicting general trends in drug movement across biological membranes and it remains a useful concept. There are numerous examples illustrating the general relationship among pH, pKa, and drug absorption developed in that hypothesis. The primary limitation of this concept is the assumption that only nonionized drug is absorbed, when in fact the ionized species of some compounds can be absorbed, albeit at a slower rate. There is also the presence of unstirred water layers at the epithelial membrane surface, which can alter the rate of drug diffusion. Furthermore, the hypothesis is based on data obtained from drug in solution. In a practical sense, other considerations may also govern the pattern of drug absorption, and these include dissolution rate from solid dosage forms, the large intestinal surface area, and the relative residence times of the drug in different parts of the GIT. These factors are discussed below. In general then, drug absorption in humans takes place primarily from the small intestine regardless of whether the drug is a weak acid or base; gastric absorption, even for acidic drugs, is minimal.

Mechanisms of Drug Absorption

Water-soluble vitamins (B2, B12, and C) and other nutrients (e.g., monosaccharides, amino acids) are absorbed by specialized mechanisms, which implies membrane participation in transport and the need for energy expenditure. With the exception of a number of antimetabolites used in cancer chemotherapy, L-dihydroxyphenylalanine (L-dopa) and certain antibiotics (e.g., aminopenicillins, aminocephalosporins), the majority of drugs are absorbed in humans by a passive diffusion mechanism. Passive diffusion indicates that the transfer of a compound from an aqueous phase through a membrane may be described by physical chemical laws and by the properties of the membrane; no energy is required. The membrane itself is passive in that it does not partake in the transfer process but acts as a simple barrier to diffusion. The driving force for diffusion across the membrane is the concentration gradient (more correctly, the activity gradient) of the compound across that membrane. This mechanism of membrane penetration may be described mathematically by Fick's first law of diffusion, which has been simplified by Riggs and discussed by Benet (30,31).

The derivative on the left side of the equation represents the rate of appearance of drug in the blood (amount/time) when the drug diffuses from the gut fluids (g) to the blood (b). The expression reads, the rate of change of the quantity Q) entering the blood stream. The other symbols have the following meanings (and units): Dm, the diffusion coefficient of the drug through the membrane (area/time); Am, the surface area of the absorbing membrane available for drug diffusion (area); ^m/aq, the partition coefficient of the drug between the membrane and aqueous gut fluids (unitless); Cg - Cb, the concentration gradient across the membrane, representing the difference in the effective drug concentration (i.e., activity) in the gut fluids (Cg) at the site of absorption and the drug concentration in the blood (Cb) at the site of absorption (amount/volume); and AXm, the thickness of the membrane (length). This equation nicely explains several of the observations discussed previously. Thus, rate of drug absorption is directly dependent on the membrane surface area available for diffusion, indicating that one would expect more rapid absorption from the small intestine compared with that from the stomach. Furthermore, the greater the membrane aqueous fluid partition coefficient (Rm/aq), the more rapid the rate of absorption, supporting the previous discussion indicating the dependence of absorption rate on Ko/w. We know that pH will produce a net effect on absorption rate by altering several of the parameters in equation (1). As the pH for a given drug will determine the fraction nonionized, the value of Rm/aq will change with pH, generally increasing as the fraction nonionized increases. Depending on the relative ability of the membrane to permit the diffusion of the nonionized and ionized forms, Cg will be altered appropriately. Finally, the value of Dm may be different for the ionized and nonionized forms of the compound. For a given drug and membrane and under specified conditions, equation (1) is made up of a number of constants that may be incorporated into a large constant (P) referred to as the permeability coefficient:

where P incorporates Dm, Am, Rm/aq, and AXm and has units of volume/time, which is analogous to a flow or clearance term. Since the volume into which the drug may distribute from the blood is large compared with the gut fluid volume, and since the rapid circulation of blood through the GIT continually moves absorbed drug away from the site of absorption, Cg ^ Cb. This is often referred to as a "sink condition," indicating a

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