Unit 1 - Biotransformation of toxicants Flashcards
(34 cards)
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
