How drugs are metabolized in the liver?
Most drugs must pass through the liver, which is the primary site for drug metabolism. Once in the liver, enzymes convert prodrugs to active metabolites or convert active drugs to inactive forms. The liver’s primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes.
What is microsomal oxidation in liver?
Liver microsomes contain an enzyme system, TPNH oxidase, which catalyzes the oxidation of TPNH by oxygen to yield TPN and hydrogen peroxide.
What do microsomal enzymes in the liver do?
Inducers of microsomal enzymes stimulate the metabolism or synthesis of several normal body substrates such as steroid hormones, pyridine nucleotides, cytochromes, and bilirubin. Evidence has accumulated that steroids are normal body substrates of drug-metabolizing enzymes in liver microsomes.
What is the Phase 1 and Phase 2 of hepatic drug metabolism?
Phase I reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Phase II reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine.
How are drugs metabolized?
Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization; whatever the process, the goal is to make the drug easier to excrete. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver.
What is liver metabolism?
Hepatocytes are metabolic overachievers in the body. They play critical roles in synthesizing molecules that are utilized elsewhere to support homeostasis, in converting molecules of one type to another, and in regulating energy balances.
What are microsomal enzymes?
Microsomal enzymes are typically found in the endoplasmic reticulum of hepatocytes. Microsomes are fragments of endoplasmic reticulum and attached ribosomes that are isolated together when homogenized cells are centrifuged.
What is microsomal oxidation process?
The microsomal ethanol oxidizing system (MEOS) is an alternate pathway of ethanol metabolism that occurs in the smooth endoplasmic reticulum in the oxidation of ethanol to acetaldehyde.
What is microsomal metabolism?
Liver microsomes are subcellular fractions which contain membrane bound drug metabolizing enzymes. Microsomes can be used to determine the in vitro intrinsic clearance of a compound. The use of species-specific microsomes can be used to enable an understanding of interspecies differences in drug metabolism.
What is microsomal drug metabolism?
Microsomal. The microsomal enzymes that metabolize drugs are localized in the smooth endoplasmic reticulum. The oxidative enzymes of this system have attracted particular attention in research. This group of enzymes has been called mixed-function oxidases or monooxygenases.
What are the 2 phases of drug metabolism?
Metabolism is often divided into two phases of biochemical reaction – phase 1 and phase 2. Some drugs may undergo just phase 1 or just phase 2 metabolism, but more often, the drug will undergo phase 1 and then phase 2 sequentially.
Can liver microsomal intrinsic clearance predict drug disposition characteristics?
Human liver microsomal intrinsic clearance has become a commonly measured parameter during drug discovery, and such data are used to design compounds predicted to possess optimal drug disposition characteristics. Liver microsomal intrinsic clearance values can be scaled and used to predict hepatic c …
Can in vivo drug metabolism be predicted from in vitro metabolism data?
(1997) Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 73:147–171. (2011) Simultaneous absolute quantification of 11 cytochrome P450 isoforms in human liver microsomes by liquid chromatography tandem mass spectrometry with in silico target peptide selection.
What are in vitro models of hepatic drug biotransformation?
Several in vitro models have been developed to study hepatic drug biotransformation, which include recombinant drug-metabolizing enzymes (DMEs), liver subcellular fractions (microsomes, cytosol, and S9 fractions), hepatic cell lines, primary hepatocytes, liver slices, and perfused livers ( Ekins et al., 2000; Brandon et al., 2003 ).
How many beta-hydroxy-THC are formed from human liver microsomes?
We have found that, in addition to catalyzing the formation of significant amounts of 7-hydroxy-THC, hepatic microsomes from nine human livers also formed 6 beta-hydroxy-THC at approximately the same rate.