Biliary clearance mechanisms

The physiological mechanisms by which phenylbutazone is cleared from the body in the horse have not been well described. In one study, renal clearance accounted for only 25% of the total drug administered (Lees et al 1985). It has been hypothesized that biliary excretion with subsequent fecal elimination represents the primary clearance mechanism of phenylbutazone in the horse (Lees et al 1985). Renal excretion, of an as yet unidentified phenylbutazone metabolite, may also account for a proportion of total body clearance of the compound. 

In recent years, in vitro models to predict biliary excretion have been introduced. Prior to that, most models involved animals whose bile ducts were cannulated or ligated. Note that renal excretion, not otherwise discussed herein, although not part of the first pass effect, is a very important clearance mechanism for small, polar molecules, in many ways acting as a counterpart to biliary excretion. 

Palmer 1989 Robinson et al.1983). However, the ratio was almost certainly affected by initial chelation with Ca-DPTA, followed by daily intravenous therapy with the chelating agent, Zn-DPTA, treatments that would have increased the urinary excretion of americium (Breitenstein and Palmer 1989). The above not withstanding, the observations made on this subject demonstrate that fecal excretion was an important pathway of excretion in this subject long after mechanical clearance of americium from the respiratory tract would have been complete. This is consistent with observations made in nonhuman primates that show that americium is excreted into bile (see Section 3.4.4.4). However, the extent to which the biliary excretion pathway in humans might resemble that of nonhuman primates is not known. 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

Sitagliptin (1) demonstrated plasma half-lives in rats, dogs, and rhesus monkeys of 1.7-4.9 h, and oral bioavailabilities of 68 100%. In rats and monkeys, clearance of 1 was relatively high (60 and 28 mL/min/kg, respectively) and was lower in dogs (6 mL/mg/kg).15 In rats and dogs, 1 was systemically cleared primarily by renal elimination of intact parent drug, with additional contributions from biliary excretion (rats) and metabolism (minor in both species).23 In rats, data suggest that active transport mechanisms are involved in the renal elimination of 1. 

Clearance and volume of distribution are two separate and independent characteristics of a drug. They are closely correlated with physiologic mechanisms in the organism (thereby the term primary parameters). Clearance defines the body s ability to remove the drug, that is, by metabolism or by renal or biliary excretion. Volume of distribution is a measure of the physical interrelationship between the drug and body constituents, such as binding to plasma proteins or partition into muscle, tissue, or fat. 

Excretion of drugs or chemicals from the body can occur through biliary, intestinal, puhnonary, or renal routes. Although each of these represents a possible mechanism of drug elimination, renal excretion is a major pathway for the ehmination of most water-soluble drugs or metabohtes and is important m TDM. Alterations in renal function may have a profound effect on the clearance and apparent half-life of the parent compound or its active metabolite(s) decreased renal function causes elevated serum drug concentrations and increases the pharmacological response. 

Clearance of almost all drugs is by renal, metabolic and/or biliary mechanisms. There are rare exceptions, such as anesthetic gases that are exhaled unchanged. However, in this chapter we shall concentrate on the typical situation. 

Cholestasis is a condition characterized by impaired flow of bile, due to physical obstruction of the biliary tree or decreased bile secretion by the liver. Cholestasis produces alterations of enzyme activity in the liver (cytochrome P450) as well as altered transporter expression, with associated effects on drug clearance. As discussed previously, cholestasis can occur through inhibition of the canalicular membrane transporter, BSEP. In response to cholestasis, however, the liver has adaptive mechanisms to minimize cellular accumulation of toxic bile salts. These include upregulation of MRP3 to increase sinusoidal efflux, and downregulation of Na -taurocholate cotransporting polypeptide (NTCP), which mediates bile salt uptake from the blood to the liver. 

Scheme 113.1 Schematic overview of cholesterol metabolism and main proposed mechanisms of action of phytosterols. 1. The absorption of dietary and/or biliary cholesterol is reduced by competition with PS for incorporation into mixed micelles. 2. Esterification of free cholesterol in the enterocyte is reduced by competition with PS for ACAT-2 enzyme. 3. Upregulation of the heterodimer ABCG5/G8 by PS can increase intestinal and hepato-biliar secretion. 4. Upregulation of ABCAl by PS can increase the incorporation of sterols into nascent HDL. 5. Increased cholesterol excretion via TICE. 6. Although it is not directly mediated by PS, the lower levels of hepatic cholesterol can lead to a lower VLDL secretion and upregulation of LDL receptor, which improves the clearance of plasma cholesterol. Abbreviations FC free cholesterol, CE cholesterol esters, ACAT-2 Acyl-CoA cholesterol O-acyltransferase 2, CM chylomicron, CMR chylomicron remnant, TICE transintestinal cholesterol efflux, LDL low-density lipoprotein, IDL intermediate-density lipoprotein, HDL high-density lipoprotein...

---