As mentioned earlier, one of the most direct methods for evaluating permeability is the isolated perfusion of the human intestine (4-7). Because some of this data will be used in this chapter, it is worthwhile to compare this method and its results with the traditional way of determining the absorption rate constant from pharmacokinetic data. From pharmacokinetics, the rate of absorption can be described by:
f = -KaM (4)
where M is the mass of drug in the GI tract. Similarly, the rate of absorption can be determined from an intestinal perfusion experiment:
f = -PAC (5)
where P is the intestinal permeability, A is the surface area of the perfused intestinal segment, and C is the drug concentration. Because drug concentration is equal to the mass of drug in the segment divided by the volume V of the segment, where r and L are the radius and the length of the perfused segment, respectively. Given an estimated radius of the human small intestine of 1.75 cm (7), the surface to volume ratio is approximately 1.1. Permeability is typically in units of cm/sec, whereas absorption rate constants are generally reported in units of reciprocal minutes or hours. Permeability can be easily converted to an absorption rate constant by multiplying its value by the surface to volume ratio and converting to desired units of time. Using propranolol as an example, its human intestinal permeability was reported as 3.878 × 10~ cm/sec (6).
This calculated absorption rate constant using permeability from human intestinal perfusion experiments compares well with the value of 0.025 min-1 reported independently from a pharmacokinetic study (8).
It should also be noted that the absorption rate constant as presented earlier has only been shown in one direction: from the lumen to the blood. In general, drugs with solubilities in the mg/mL range will exist in the mg/mL range in the GI tract. Blood concentrations are generally in the |jLg/mL range. Therefore, the reverse absorption rate constant would have to be approximately 1000-fold higher to be significant. If the drug is poorly soluble, in the /Ag/mL range, blood concentrations are likely to be in the ng/mL range. Again, the reverse rate would have to be 1000-fold higher to be comparable to the forward rate. For the remainder of this chapter, the reverse rate will be ignored while acknowledging that this assumption is open to debate (9,10).
In reality, most dosage forms are tablets containing a crystalline powder of the drug substance. Unlike a solution dose, the amount of drug dissolved in the intestine will increase with time, as the dosage form disintegrates and releases crystalline drug particles. There are no simple pharmacokinetic equations to describe this process. Solution dosage forms of the same drug are unlikely to show differences in the rate and extent of absorption and, therefore, are likely to be bioequivalent. Solution dosage forms will present the total dose in the form of drug that can be absorbed (in solution) with the amount of drug in the lumen falling exponentially, as drug is absorbed at the same rate. However, immediate-release solid dosage forms are likely to have slightly different rates of disintegration due to the choice of tablet excipients and the manufacturing process and potentially larger differences in dissolution rate depending on the drug particle size and the efficiency of wetting provided by the formulation.
There is a mechanistically based theory to describe the kinetics of dissolution that will be discussed, and it will be shown how dissolution theory can be used to determine if the combined effect of disintegration and wetting are having a significant impact on drug absorption. Before getting into the more sophisticated treatment of dissolution, the absorption rate equation discussed earlier provides the starting point for a very simple and useful analysis of situations that might present difficulties in drug absorption. Recalling Equation 2, the integration of this equation over a specified period of time gives the mass of drug absorbed from the GI tract. If nothing limited the amount of drug that could be administered as a solution to the GI tract, then there would be no limit to the amount of drug that could be absorbed. However, drug solubility presents a limit to the amount of drug that can exist as a solution in the GI tract. Any solid crystalline drug administered would continue to dissolve unless its concentration equalled its solubility. At this point, no further drug would dissolve until some of the drug in solution was absorbed. If enough solid drugs were administered so that the rate of dissolution was equal to the rate of absorption, a temporary steady state would exist where the concentration of drug in the GI tract would be equal to the solubility of the drug.
