5 The main routes by which drugs and their metabolites leave the body are: -Kidney-Hepatobiliary system-LungsMost drugs leave the body in the urine, either unchanged or as polar metabolitesSome drugs are secreted into bile via the liverBut most are reabsorbed from the intestine .
6 Drug metabolismDrug metabolism involves two kinds of biochemical reaction known as phase I and phase II reactionsPhase II reactions:Conjugation(e.g. glucuronidation) of a reactive group (often inserted during phase I reaction ) usually forms inactive and readily excretable products.Phase I reactions:OxidationReductionHydrolysisInduction of enzymes by other drugs and chemicals can greatly accelerate hepatic drug metabolism (Drug interaction)
7 DetoxificationDef: Bio-transformations which eliminate the toxicant or prevent its formationIn some cases, detoxification may compete with toxication for a chemicalDetoxification can take several pathways, depending on the chemical nature of the toxic substance
8 Detoxification of toxicants with no functional groups: In general, chemicals without functional groups, such as benzene and toluene, are detoxicated in two phases-initially, a functional group such as hydroxyl or carboxyl is introduced into the molecule, most often by cytochrome P-450 enzymes.-subsequently, an endogenous acid such as glucuronic acid, sulfuric acid, or an amino acid is added to the functional group by a transferase. With some exceptions, the final products are in active, highly hydrophilic organic acids that are readily excreted.
9 Detoxification of nucleophiles: Nucleophiles generally are detoxificated by conjugation at the nucleophilic functional group.Hydroxylated compounds are conjugated by sulfation or glucuronidation.Thiols are glucuronidatedAmines and hydrazines are acetylated.These reactionsprevent peroxidase-catalyzed conversion of the nucleophiles to free radicalsbiotransformation of phenols, aminophenols, catechols, and hydroquinones to electrophilic quinines and quinoneimines.
10 Detoxification of electrophiles: A general mechanism is conjugation with the thiol nucleophile glutathioneSpecific mechanisms for the detoxication of electrophilic substances include epoxide hydrolyase-catalyzed biotransformation of epoxides and arene oxide to diols and dihydrodiols, respectively
11 Detoxification of free radicals: Peroxidase-generated free radicals are eliminated by electron transfer from glutathione. This results in the oxidation of glutathione, which is reversed by NADPH-dependent glutathione reductase. Thus, glutathione plays an important role in the detoxication of both electrophiles and free radicals
12 When detoxification fails: 1-Toxicants may crush detoxification processes, leading to exhaustion of the detoxication enzymes, consumption of their co-substrates or depletion of cellular antioxidants such as glutathione, ascorbic acid, and a-tocopherol. This results in the accumulation of the ultimate toxicant. 2- Liver Diseases. 3- Some conjugation reactions can be reversed. For example: 2-naphthylamine, a bladder carcinogen, is N-hydroxylated and glucuronidated in liver, with the glucuronide excreted