tailieunhanh - Color Atlas of Pharmacology (Part 4): Drug Elimination

Compared with hydrophilic drugs not undergoing transport, lipophilic drugs are more rapidly taken up from the blood into hepatocytes and more readily gain access to mixed-function oxidases embedded in sER membranes. For instance, a drug having lipophilicity by virtue of an aromatic substituent (phenyl ring) (B) can be hydroxylated and, thus, become more hydrophilic (Phase I reaction, p. 34). Besides oxidases, sER also contains reductases and glucuronyl transferases. The latter conjugate glucuronic acid with hydroxyl, carboxyl, amine, and amide groups (p. 38); hence, also phenolic products of phase I metabolism (Phase II conjugation). Phase I and Phase II. | 32 Drug Elimination The Liver as an Excretory Organ As the chief organ of drug biotransformation the liver is richly supplied with blood of which 1100 mL is received each minute from the intestines through the portal vein and 350 mL through the hepatic artery comprising nearly 1 3 of cardiac output. The blood content of hepatic vessels and sinusoids amounts to 500 mL. Due to the widening of the portal lumen intrahepatic blood flow decelerates A . Moreover the endothelial lining of hepatic sinusoids p. 24 contains pores large enough to permit rapid exit of plasma proteins. Thus blood and hepatic parenchyma are able to maintain intimate contact and intensive exchange of substances which is further facilitated by microvilli covering the hepatocyte surfaces abutting Disse s spaces. The hepatocyte secretes biliary fluid into the bile canaliculi dark green tubular intercellular clefts that are sealed off from the blood spaces by tight junctions. Secretory activity in the hepatocytes results in movement of fluid towards the canalicular space A . The hepatocyte has an abundance of enzymes carrying out metabolic functions. These are localized in part in mitochondria in part on the membranes of the rough rER or smooth sER endoplasmic reticulum. Enzymes of the sER play a most important role in drug biotransformation. At this site molecular oxygen is used in oxidative reactions. Because these enzymes can catalyze either hydroxylation or oxidative cleavage of -N-C- or -O-C-bonds they are referred to as mixedfunction oxidases or hydroxylases. The essential component of this enzyme system is cytochrome P450 which in its oxidized state binds drug substrates RH . The Fen -P450-RH binary complex is first reduced by NADPH then forms the ternary complex O2-Fen-P450-RH which accepts a second electron and finally disintegrates into Feln-P450 one equivalent of H2O and hydroxylated drug R-OH . Compared with hydrophilic drugs not undergoing transport lipophilic drugs are more rapidly taken