Therapeutic Applications of ASBT

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The uses of carrier-mediated bile acid for drug delivery purposes can be divided in three groups: liver- and gallbladder-directed delivery, oral absorption enhancement, and lowering serum cholesterol. Oral absorption enhancement can be directed to either the liver or gallbladder or systemic delivery.

5.5.3.5.1 Liver and Gallbladder Delivery. So far, most studies have focused on using the bile acid transport system for liver targeting. The research groups of Kramer (287-289) and Stephan (290) have successfully shown specific hepatic delivery of chlorambucil, HMG-CoA reductase inhibitors, and l-T3, respectively. These studies prove that the coupling of drug entities to bile acids does not cause a loss of affinity for the hepatic bile acid carrier. Apart from the necessity of a negatively charged group around the C-24 position, Kim and colleagues (291) have shown that some size restrictions apply when compounds are coupled to the C-3 position. Both the 3-posi-tion and the 24-position appear to be usable coupling points for a prodrug strategem. The 24-position appears to be an attractive site in the bile acid molecule for coupling purposes. The carboxylic acid moiety is easily linked to an amine using conventional peptide-synthe-sizing techniques (292-294), making the synthesis of these compounds relatively easy. It should be stressed, however, that the need for a negatively charged group around the C-24 position is required.

5.5.3.5.2 Systemic Delivery. When one compares the maximal transport flux (t/max) values of taurine conjugated bile acids measured in rat liver and distal ileum, a trend for relatively higher hepatic maximal transport rates can be observed. This observation can have important consequences when using the bile acid transporter for oral drug delivery. By use of a prodrug approach, with a bile acid molecule as a shuttle, liver targeting is easily accomplished, whereas systemic drug delivery needs to address the problem of rapid biliary excretion. Thus far, no single study has unequivocally shown the release of the parent compound from the conjugate after passage across the intestinal wall. It has to be mentioned, however, that no studies so far have attempted to develop a prodrug approach in which the drug will be released before arrival in the liver. In that case, the drug moiety must be released from the bile acid it is coupled to, within either the enterocyte or the portal vein. Only if these conditions are met, will systemic delivery using a prodrug approach be successful. Although promising, the suitability of this transport system for systemic drug delivery remains to be demonstrated.

5.5.3.5.3 Cholesterol-Reducing Agents. Hy-percholesterolemia is well known as a major risk factor for coronary heart disease. In clinical practice, two main hypocholestrolemic agents are commonly used. One is the 3-hy-droxy-3-methylgrutaryl coenzyme A (HMG-CoA) reductase inhibitors (such as Lipitor); another is the bile acid sequestrants, such as cholestyramine and colestipol (97), which bind bile acid in the intestinal lumen and thus increase their excretion. The main drawback of

OMe S-8921

Figure 8.13. Structure of specific bile acid transporter inhibitors. See text for additional details.

OMe S-8921

Figure 8.13. Structure of specific bile acid transporter inhibitors. See text for additional details.

these agents is poor compliance of patients stemming from adverse side effects, such as high dosages of 10-30 g per day, constipation, maldigestion, and malabsorption syndromes. As an alternative method to bile acid séquestrants, any reagent that can inhibit the bile acid active transport system could block the reabsorption of bile acids and consequently reduce the serum cholesterol level. So far, several molecules have been found to possess this effect in animal studies (108-110,295).

The first such inhibitors consisted of the coupling of two bile acid molecules by means of a spacer to allow simultaneous interaction with more than one transporter site, resulting in an efficient inhibition of bile acid reabsorption without or with only low absorption of the inhibitor itself (110) (Fig. 8.13). Recently, it was shown that a benzothiazepine derivative, 2164U90, was able to selectively inhibit active ileal bile acid absorption in rats, mice, mon keys, and humans (296, 297). Similarly, another compound, S-8921 (Fig. 8.13), a lignan derivative, was able to reduce serum cholesterol in hamsters, mice, and rabbits. The inhibition of the intestinal bile acid transport system is thought to be the underlying mechanism for an increased fecal bile acid excretion and lower plasma LDL cholesterol levels after oral administration of these drugs.

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