Enterohepatic Cycle

After an orally ingested drug has beenabsorbed from the gut, it is transportedvia the portal blood to the liver, where itcan be conjugated to glucuronic or sul-furic acid (shown in B for salicylic acidand deacetylated bisacodyl, respective-ly) or to other organic acids. At the pH ofbody fluids, these acids are predomi-nantly ionized; the negative charge con-fers high polarity upon the conjugateddrug molecule and, hence, low mem-brane penetrability. The conjugatedproducts may pass from hepatocyte intobiliary fluid and from there back intothe intestine. O-glucuronides can becleaved by bacterial inthe colon, enabling the liberated drugmolecule to be reabsorbed. The entero-hepatic cycle acts to trap drugs in thebody. However, conjugated productsenter not only the bile but also theblood. Glucuronides with a molecularweight (MW) > 300 preferentially passinto the blood, while those with MW >300 enter the bile to a larger extent.Glucuronides circulating in the bloodundergo glomerular filtration in the kid-ney and are excreted in urine becausetheir decreased lipophilicity preventstubular reabsorption.Drugs that are subject to enterohe-patic cycling are, therefore, excretedslowly. Pertinent examples include digi-toxin and acidic nonsteroidal anti-in-flammatory agents.Conjugations (B)The most important of phase II conjuga-tion reactions is glucuronidation. Thisreaction does not proceed spontaneous-ly, but requires the activated form ofglucuronic acid, namely glucuronic aciduridine diphosphate. Microsomal glucu-ronyl transferases link the activatedglucuronic acid with an acceptor mole-cule. When the latter is a phenol or alco-hol, an ether glucuronide will beformed. In the case of carboxyl-bearingmolecules, an ester glucuronide is theresult. All of these are O-glucuronides.

Amines may form N-glucuronides that,unlike O-glucuronides, are resistant tobacterial Soluble cytoplasmic sulfotrans-ferases conjugate activated sulfate (3’-phosphoadenine-5’-phosphosulfate)with alcohols and phenols. The conju-gates are acids, as in the case of glucuro-nides. In this respect, they differ fromconjugates formed by acetyltransfe-rases from activated acetate (acetyl-coenzyme A) and an alcohol or a phenol.Acyltransferases are involved in theconjugation of the amino acids glycineor glutamine with carboxylic acids. Inthese cases, an amide bond is formedbetween the carboxyl groups of the ac-ceptor and the amino group of the do-nor molecule (e.g., formation of salicyl-uric acid from salicylic acid and glycine).The acidic group of glycine or glutamineremains free.