Role of Transporters in Drug Absorption

As described in Chapter 4, oligopeptide and mono-carboxylic acid transporters facilitate the absorption of certain drugs. There have been a number of demonstrations that these natural transport pathways can be exploited to enhance drug action. An example demonstrating this concept is the discovery that valacyclovir is a substrate for the PEPT-1 transporter (81). Valacyclovir is an amino acid ester prodrug of the antiviral drug acyclovir. The usefulness of acyclovir is somewhat limited by its poor bioavailability. However, the oral bioavailability of valacyclovir is increased three- to fivefold in humans. Experiments using a rat intestinal perfusion model demonstrated a 3- to 10-fold increased intestinal permeability of valacyclovir over acyclovir. The effect was specific (i.e., exhibited structure-activity preferences among a family of amino acid ester prodrugs), and was stereospecific for l-valine, saturable, inhibitable by known PEPT-1 substrates (cephalexin, dipeptides), and competitive with other amino acid ester prodrugs (e.g., Glyacyclovir, Val-AZT). Studies using Chinese hamster ovary (CHO) cells expressing hPEPT-1 demonstrated competition between valacyclovir and the classic PEPT-1 substrate [3H]glycylsarcosine. Experiments in Caco-2 cells showed enhanced, saturable, and inhibitable mucosal to serosal transport, consistent with active transport via the PEPT-1 transporter. In contrast, serosal to mucosal transport was shown to be by passive diffusion. Furthermore, transport was accompanied by hydrolysis of the prodrug, such that although drug was taken up as valacyclovir, it appeared on the serosal side as acyclovir. Following up the valacyclovir-PEPT-1 discoveries, valganci-clovir was developed to exploit the same delivery strategy (82). In a clinical trial for cytomegalovirus prophylaxis, a daily oral dose of 900 mg valganciclovir was as effective as a daily 1-hour intravenous infusion of 5 mg/kg ganciclovir at (83, 84).

These examples are unusual in that valacyclovir is an amino acid ester of a nucleoside that does not closely resemble the normal dipeptide substrates of the PEPT-1 transporter. A number of other drugs (such as methotrexate) are probably transported by proteins that normally transport the metabolites that they resemble and antagonize (e.g., folates). However, these cases represent fortuitous examples of drug transportability "natural selection" during the drug discovery and development process. With increased understanding of the specificity determinants of nutrient transport, a rational basis for designing or redesigning drugs to exploit specific transporters may emerge. For example, XP13512 is a prodrug of gabapentin, which is beginning Phase II clinical trials. Absorption of gabapentin is limited by saturation of relevant small intestinal amino acid transporters. XP12512, which is metabolized to gabapentin in the intestine and liver, has a sustained action due to its ability to use several uptake transporters located in the large as well as the small intestine (85, 86).

As discussed in Chapters 4 and 15, both P-gp and CYP3A4 are colocalized in intestinal epithelial cells and may limit bioavailability either by intestinal firstpass metabolism by CYP3A4 or by P-gp-mediated exsorption. Many of the substrates for CYP3A4 are also substrates for P-gp (see Table 4.2), so that many CYP3A4 substrates may also be competing for transport by P-gp or may modify its level of expression (87). There is no sequence homology between these proteins and likely no tertiary structural homology. However, both likely have similar broadly accessible hydrophobic pockets.

Competition between substrates for limiting transporter molecules and other effects lead to drug-drug, drug-food, and drug-dietary supplement interactions very similar to those seen with CYP450s. In an explicit test of GI absorption/exsorption interactions, small intestinal secretion of intravenously infused tal-inolol, a b1-adrenergic receptor antagonist, has been studied in healthy volunteers using a steady-state perfusion technique (88). Perfusion of dexverapamil [(-R)-verapamil] into the intestinal lumen lowered the intestinal secretion of talinolol 29-56%. The conclusion is that bioavailability of talinolol is in part limited by exsorption and may be subject to drug interactions during absorption. In this study (_R)-verapamil was used because it is known to affect P-gp-mediated drug transport, but is devoid of the pharmacological effects of (S)-verapamil. Hence, it can be used safely as a probe in clinical studies of P-gp inhibition. P-gp can be activated as well as inhibited, as evidenced by the ability of grapefruit juice to increase P-gp activity, partially counteracting its inhibition of CYP3A4-mediated first-pass metabolism (89, 90).

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