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Lecture:3
Toxicokinetic: Biotransformation of
toxicants
Dr Hanouf Bafhaid
hsbafhaid@uqu.edu.sa
D e p a r t m e n t o f P h a r m a c o l o g y a n d To x i c o l o g y
College of Pharmacy
Umm Al-Qura University
Learning outcome
At the end of this lecture, you will be able to:
Identify the key compartments that determine the fate of toxicants in the body
Explain the different transports system of toxicants and factors affecting absorption
Absorption pathways:
-Gastrointestinal, respiratory, and dermal systems
-These systems are lined with epithelia that present significant
barriers to the entry of foreign substances due to tight junctions
between their cells or continuous lipid layers in the case of skin
1-Size
-Molecules with a molecular mass of 500 Da or less penetrating cell membranes in a process
known as passive diffusion (transcellular permeability)
-Small molecules (150 Da or less) that are highly water soluble may enter tissues via filtration
(paracellular permeability)
-A significant pH gradient exists throughout the gastrointestinal tract (e.g. from pH 1 2 in the stomach to pH 5 6 in the duodenum and
pH 8 in the ileum and colon), the ionisation state of ingested molecules frequently changes as they transit through this organ.
-Majority of toxicants absorption occurs in zones where the molecule assumes a neutral pH, for most molecules the duodenum remains
the main site of GI-tract absorption due to its large surface area and high blood flow
-Acidic compounds are (i.e. low pKa) nonionised within the acidic gastric environment. Basic compounds are nonionised within the
neutral pH environment prevailing within the small intestine
Distribution
A process by which toxicants move throughout the body and reach their site of action
-Xenobiotics may distribute into any or all of the fluid compartments: plasma, interstitial fluid and intracellular fluid
Volume of distribution:
The xenobiotic metabolizing enzymes can be divided into two main groups:
1. Non-microsomal enzymes present in the cytoplasm, plasma, and mitochondria and occur mainly in liver and GI tract
These enzymes catalyse few oxidative, hydrolytic and conjugative reactions
2. Microsomal enzymes are present in the smooth endoplasmic reticulum of liver and other tissues and classified into
phase I and II metabolism
Metabolism
Xenobiotic metabolism is classified into 2 types:
Phase I: increase polarity
Function: adding or exposing a functional group
Reactive group: -OH, -SH, -NH2, or -COOH
Reaction: oxidation, reduction, hydrolysis
Enzyme: CYP450, flavin monooxygenases (FMO), hydroxylase, alcohol and aldehyde dehydrogenase, carboxylesterases
Activity of metabolite: variable (increase or decrease)
-Major human CYP isoenzymes: Figure 5. Estimate of CYP isoenzymes contribution to xenobiotic
metabolism Copyright (2008, American Chemical Society)
CYP3A4/5 is most important during the metabolism of drugs
CYP2E1 metabolises many synthetic chemicals of relevance to toxicology
Metabolism
Phase I reaction
Table 1: Types of phase I biotransformation reactions (oxidation) with examples
A. Oxidation: it is the most common reaction, proceed by adding oxygen to a foreign compound/by removing hydrogen atoms from a
molecule add functional group,
Types of reactions functional modification Reaction (example)
Table 2: Types of phase I biotransformation reactions (reduction and hydrolysis) with examples
B. Reduction: is acceptance of one or more electrons(s) from another substrate by the addition of extra
hydrogen atoms to a molecule (or the removal of oxygen atoms) mask a functional group
-The bioactive metabolites interact with the body tissues cause toxicities such as carcinogenesis, teratogenesis, and tissue necrosis.
-The bioactivation reactions are generally catalysed by cytochrome P450- dependent mono-oxygenase systems, some other enzymes are
involved e.g. those in intestinal flora
-The reactive metabolites primarily belong to three main categories: electrophiles and free radicals
-Electrophiles Molecules which are deficient in electrons pair with a positive charge, react by sharing electron pairs with electron-rich
atoms in nucleophiles
-Free radicals molecules contain one or more unpaired electrons (odd number of electrons) in their outer orbit
-Both electrophiles and free radicals irreversible binding with proteins, nucleic acids, and lipids cause damage to DNA and protein, lipid
peroxidation and carcinogenesis
-Xenobiotics may decrease the activity of liver microsomal enzymes (CYP450) phase I
-The administration of hepatotoxic agents causes either an increase in the rate of enzyme degradation or a decrease in
the rate of enzyme synthesis
-Decrease metabolism increase activity or toxicity of drugs
-CYP2D6 polymorphisms
Patient subgroups that display exaggerated responses to the cardiovascular drugs debrisoquine.
The inability to metabolise debrisoquine was linked to a 2D6 polymorphism that was found to vary in its
prevalence in different ethnic groups (e.g. 5 , while the incidence in
Asian populations is ~ 1 %)
Excretion
A process by which toxicants and/or their metabolites are irreversibly transferred from body to external environment
-Route of excretion: renal, bile, lung, enterohepatic circulation
-Other routes of excretion: sweat, saliva, breast milk
Elimination kinetics
First order kinetics (majority of drugs): rate of elimination is directly proportional to drug concentration (Clearance
remain constant)
Zero order kinetics - linear (Few of drugs): rate of elimination remains constant irrespective of drug concentration
(clearance decreases with increase in drug concentration)
Excretion
1-Renal excretion
Renal excretion occurs by three different mechanisms:
1-Glomerular filtration (most xenobiotics): unbound molecules are filtered in this manner
2- Active tubular (carrier mediated process) secretion of ionized substances in the proximal tubules
3- Passive tubular reabsorption of unionized substances can be altered by changes in the pH
Biliary excretion:
Drugs are actively transported into bile
Drugs must be above the M. wt. of 500 Da to be excreted
3-Enterohepatic circulation
Substances that are metabolized in the liver, excreted into the bile, and passed into the
intestinal; they are reabsorbed across the intestinal mucosa and returned to the liver via portal
circulation
Consequence:
-Pharmacological activation/inactivation of compound
-Toxicological activation
-Drug interaction
Figure. 7 Enterohepatic circulation process
References
Goldfrank's Toxicologic Emergencies, 11th edition, 2015 by Lewis S. Nelson