Characterize Permeability

There are several techniques to characterize permeability before going into human clinical studies, including rat intestinal perfusions, Caco-2 permeability (1), and parallel artificial membrane permeability assay (PAMPA) (2). However, one should be careful in considering whether the values are useful inan absolute sense or only in a relative sense. Clinically determined human absorption rate constants serve as a good reality check for comparison. There are a largenumber of clinical studies that have been done, which include some estimate ofthe absorption rate constant (3). The upper end of the range appears to be in theneighborhood of 0.1 min21, placing the shortest absorption half-life around sevenminutes. Although there might be reports of individual patients having highervalues, it would be rare that population averages exceed this value. Typically,if an intravenous dosing leg of a clinical study has been done in addition to anoral leg, then an observed absorption rate constant can be determined aftercorrecting for bioavailability. As a word of caution, some reported absorptionrate constants might be smaller than the true intrinsic absorption rate constantsdue to the influence of dosage form disintegration and drug dissolution. Correctingobserved absorption rate constants for the effect of dissolution was part of themotivation for the author of this chapter in developing more sophisticated dissolution models so that surrogate methods could be validated against a moreaccurate data base of clinically determined absorption rate constants.As mentioned earlier, one of the most direct methods for evaluatingpermeability is the isolated perfusion of the human intestine. Becausesome of this data will be used in this chapter, it is worthwhile to compare thismethod and its results with the traditional way of determining the absorptionrate constant from pharmacokinetic data.Given an estimated radius of the human small intestine of 1.75 cm, the surfaceto volume ratio is approximately 1.1. Permeability is typically in units of cm/sec,whereas absorption rate constants are generally reported in units of reciprocalminutes or hours. Permeability can be easily converted to an absorption rateconstant by multiplying its value by the surface to volume ratio and convertingto desired units of time. Using propranolol as an example, its human intestinalpermeability was reported as 3.8781024 cm/sec. This calculated absorption rate constant using permeability from human intestinal perfusion experiments compares well with the value of 0.025 min21 reported independently from a pharmacokinetic study.It should also be noted that the absorption rate constant as presented earlierhas 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 inthe GI tract. Blood concentrations are generally in the mg/mL range. Therefore,the reverse absorption rate constant would have to be approximately 1000-foldhigher to be significant. If the drug is poorly soluble, in the mg/mL range,blood concentrations are likely to be in the ng/mL range. Again, the reverserate 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.