Unit 1 - Biotransformation of toxicants Flashcards
what can biotransformation of toxicants affect?
- route of administration
- dose
- effectiveness
- toxicity, safety
- duration of effect
what are the 2 purposes of biotransformation?
it’s a method of clearing drug from the plasma, but rate depends on endogenous enzyme systems
- drug detoxification - change structure, thus change activity
- prepare drug for excretion - reduce drug characteristics that make it easy to absorb
- make drug bigger
- add positive/negative charges
- make drug water solution (especially important)
what are the sites of biotransformation?
liver -on cellular structural components, SER, lipid environment (enhances equilibrium and accumulation with lipid soluble drugs) -mitochondria -cytoplasm anywhere else in the body
hepatic microsomal drug metabolizing systems?
in the SER
- both Phase I and Phase II processes
- -inhibition - use a drug to block metabolism of another drug or endogenous compound
- -induction - increase metabolism of primary drug or other drugs due to feedback to the nucleus; might be observed as increase in first pass metabolism
non-microsomal drug metabolizing systems?
other organs, plasma, and RBC that aren’t the liver
- only Phase I
- only inhibition b/c no nucleus to feedback to
- acetyl cholinesterase, alcohol dehydrogenase
are enzyme systems specific of broad?
both, but more likely nonspecific with a broad range of activity for classes or types of molecules
-follow concept of mass action; accumulation of products from phase I become substrates of phase II
what are phase I reactions?
drug oxidations that add O2 or change proportion of O2 in the molecule
-very important and most common metabolic transformation
how does the ER and cytoplasm of liver cells, and the mitochondria of adrenergic nerves, oxidize drugs?
by adding O2
- ER: phenobarbital –> hydroxyphenobarbital
- cytoplasm: ethanol –> acetaldehyde
- mito: norephinephrine –> 3,4 dihydroxymandelic aldehyde
what are the components of the hepatic mixed function oxidase system and what do they usually do?
- NADPH
- cytochrome P450 reductase (flavoprotein)
- cytochrome P450 (hemoproteins)
- Mg++
- phospholipid
- O2
usually metabolize lipid soluble drugs; drug as a [substrate] will concentrate in SER
what are the different groups of P450 in humans?
12 different ones
- some for toxins, others for endogenous compounds
- low specificity
- very large genetic variations
- catalyzes reductions and oxidations
- thus if giving a different drug, make sure it’s metabolized by a different P450 system
go into more detail about CYP2D6
-how many drugs are metabolized by it?
type of P450 with the largest degree of identified genetic variations
- about 70 nucleotide variations exist, resulting in inactive enzyme or reduced catalytic activity
- 65 commonly used drugs metabolized
what are the 4 phenotypes of patients for metabolic activity, and variations by race?
- poor –> potential toxicity
- intermediate
- extensive
- ultrarapid –> potentially no effect due to high first pass metabolism
5-10% of Caucasians have poor metabolism, while 1-2% of SE Asians
how can there be slow metabolism in regards to the P450 enzymes?
potential drug interactions when various drugs are metabolized by the same type of cyt P450
- competition with inhibition causes potential toxicities
- induction –> decreased effectiveness for a given dose
- this is why you should use a drug that uses a different P450 for metabolism - disease factors (liver disease, liver perfusion)
- age and sex (fetal to geriatric)
what are 10 drug biotransformations carried out by hepatic mixed funciton oxidase system?
- aliphatic oxidations
- aromatic oxidations
- oxidative N-dealkylations
- oxidative O-demethylations
- oxidative S-dealkylations
- oxidative deaminations
- N-oxidations
- N-hydroxylations
- sulfoxide formations
- oxidative desulfurations
what are drug reductions? examples in the liver microsomes, and cytoplasm/mitcohondria of liver
add H or change proportion of H in the molecule
- reduction of aromatic nitro compounds and aromatic azo compounds in hepatic/liver microsomes
- reductions of aldehydes to alcohol in cytoplasm/mitochondria of liver
what are drug hydrolysis?
cleave a molecule by adding water
how is activity in phase I reactions?
activities of drugs VS activities of metabolites
- phase I may have variable results on activity
- both in target tissue and on secondary receptors in other tissues - toxicity
what are phase II reactions generally?
conjugation in liver; synthesize a new molecule by combining drug or metabolic product of Phase I with a molecule provided by the cell
- metabolic energy is used and covalent bond is formed
- resulting molecule is larger, charged, water soluble, and inactive
what are 8 types of conjugation?
- glucuronide formation
- glycine conjugation
- glutamine conjugation
- acetylation, acylation
- sulfate conjugation
- methylation
- riboside and riboside phosphate formation
- mercapturic acid formation
when are biotransformation enzyme systems rate limiting steps?
- when metabolism is more important than renal elimination (lipid soluble drugs)
- when enzyme is relatively slow
first order VS zero order enzyme systems
first: [D] constant such that [D] «_space;Km (efficient enzyme system)
- most are first order
zero: [D]»_space; Km (inefficient enzyme system)
- at max, constant rate
how do hepatic microsomal enzymes and non-microsomal enzymes differ?
microsomal has induction (increase metabolism by drug in question, or by other drugs), inhibition (decrease metabolism by another drug), and saturation
non-microsomal has only inhibition and saturation
what is the most important route of elimination of drug or metabolites?
renal excretion
what is the equation for amount of drug excreted?
excreted = amount entering tubule - amount reabsorbed
what are the two methods drugs enter the nephron?
- glomerular filtration - only free drug molecules are filtered
- amount filtered depends on glomerular blood flow and free drug concentration - active tubular secretion - one system for acids, and one for bases (exists for endogenous compounds like uric acid or choline)
- inhibition is usually competitive (some require lots of drug before effect begins)
- saturation (can occur at therapeutic doses or with overdoses; changes from first order to second order)
do all water or lipid soluble drugs have to be conjugated by the liver?
water-soluble drugs do NOT have to be conjugated, and can go straight to kidney filtration
lipid soluble drugs MUST be conjugated by the liver
-they can go to the kidney first, but they will have back-diffusion dependent on pH of tubulus fluid
how are drugs reabsorbed in the kidney?
- passive reabsorption - especially for lipid soluble drugs
- after free water absorption, these are concentrated in the LoH
- reverse concentration gradient occurs - active reabsorption - active transport, for endogenous compounds, works for some drugs (like glucoes)
what is the equation for amount of drug excreted?
amount of drug excreted = glomerular filtration + active tubular secretion - passive reabsorption - active reabsorption
how does one enhance renal excretion?
- forced diuresis
- manipulate pH of urine to trap ionized drug
- usual urine pH is 5.5, so if alkalinize urine, increased clearance of acidic drugs
explain biliary excretion
enters bile by secretion (active transport system with acids/bases) or passive diffusion
reabsorbed by passive diffusion and original absorption mechanism (enterohepatic cycling can occur)
what is the use of activated charcoal?
given to overdose patients to drink, so it binds lipid soluble drugs in the stomach to facilitate clearance
what are non-kidney/bile methods of elimination?
lung (exhaled air), sweat, saliva, tears, and breastmilk
what is the main purpose of elimination of drugs from the site of action? what are the 3 steps?
decrease concentration of drug in the plasma
- redistribution - changes location of drug
- biotransformation - primarily hepatic, metabolically changes drug to metabolites, and causes clearance of drug from plasma
- excretion - primarily renal, produces clearance of drug from plasma and body
what are 6 factors that influence clearance?
- body surface area
- protein binding
- cardiac output
- renal function
- hepatic function
- blood flow to systemic organs
