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- chemical alteration of a small drug's structure (larger molecules undergo catabolism)
- leads to changes in a drug's physical properties & biological effects
- (in contrast to drug transport, where NO molecular alteration usually takes place)
What are many drugs made up of?
- racemic mixtures
- enantiomers may have different biological properties, eg the R-form is active while the S-form is inactive
- R- & S-forms may have different rates/mechanisms of metabolism
- each form may be a substrate for DIFFERENT enzymes
What is an example of a commonly used drug that may cause significant toxicity due to production of a toxic metabolite?
- can cause hepatotoxicity - is the leading cause of fatal drug-induced liver damage
- normally done by detoxification/conversion (conjugation) to the non-toxic metabolite glucuronide sulfate
- a side metabolic pathway is mediated by CYP450 enzymes yielding the toxic intermediate NAPQI (N-acetyl-p-benzoquinone imine)
NAPQI (N-acetyl-p-benzoquinone imine)
- toxic metabolite of acetaminophen produced by CYP450 enzymes
- may cause hepatic cell death, but since it is normally produced in small quantities it is usually conjugated to glutathione and excreted before harm can be done
- *when large amounts of NAPQI are formed, the capacity for glutathione conjugation can be exceeded
What are some risk factors for hepatotoxicity from acetaminophen?
- high doses of acetaminophen
- taking acetaminophen + inducers of the CYP450
- system (eg. alcohol, anticonvulsants, carbamazepine, phenytoin, rifampin)
- someone who has preexisting liver disease
- someone w/ with poor nutritional status (aka low levels/stores of glutathione)
What's one way to treat patients who have overdosed on acetaminophen?
- N-acetylcysteine, NAC (Mucomyst, Acetadote)
- it's a precursor of glutathione
- giving the drug within 16-24 hours of overdose can significantly reduce liver damage
What is the usual purpose of drug metabolism?
- to make the foreign chemicals more POLAR (water-soluble) so they can be excreted in the urine
- drugs are engineered to be lipophilic so they can cross through cell membranes & be absorbed into target sites
- once metabolized at their target site, the resulting metabolites are ideally more polar, so that elimination may occur
What are the different type of metabolites that can result from drug breakdown/metabolism?
- 1. pharmacologically inactive
- 2. pharmacologically active (similar to the parent)
- 3. toxic (unlike the parent drug, can cause necrosis)
multi-drug resistance-associated protein
uridine diphosphate glucuronosyltransferase
smooth endoplasmic reticulum cytochrome P450
- a type of drug that is inactive until metabolized, at which point its metabolite has significant pharmacologic activity
- eg. Plavix (clopidogrel) is a platelet activity inhibitor only active when converted by CYP450 enzymes
- eg. Codeine has antitussive effects but is a weak analgesic; becomes analgesic when turned into its metabolite morphine
- an enzyme from the CYP450 family that metabolizes about 10% of codeine into morphine, which causes most of the analgesic benefit derived from a dose of codeine
- * 6-7% of the population lack an active form of CYP2D6, meaning they do not experience pain relief from codeine b/c they cannot convert it into morphine
- (on the other hand people who over-express CYP2D6 are more sensitive to codeine)
What are the different categories of enzymes that may participate in metabolism?
- 1. smooth endoplasmic reticulum (microsomal)
- 2. cytosol
- 3. mitochondria (P450 enzymes involved with other things besides drug metabolism)
- 4. lysozymes
What types of enzymes participate in microsomal (SER) metabolism?
- cytochromes P450 (CYPs)
- NADPH-CYP reductase
- UDP glucuronosyltransferases (UGT)
- Glutathione S-transferases
- epoxide hydrolases
- flavin-containing monooxygenases (FMOs)
- carboxyl esterases
- aldehyde dehydrogenases
What factors influence the activity of a drug-metabolizing enzyme?
- 1. genetics (polymorphisms in processes such as acetylation, or in cytochrome activity such as those sometimes seen with CYP2D6 and CYP2C19)
- 2. disease states (liver full of fibrosis)
- 3. habits (eg. smoking, exercising)
- 4. diet (eg. grapefruit juice inhibits CYP450 in the intestine)
- 5. environment
- 6. age
- 7. gender
- *biggest intrinsic factor is genetics; biggest extrinsic factor is drug-drug interactions
drug-metabolizing enzyme polymorphisms
- a few have predictable consequences in terms of systemic exposure & clinical drug sensitivity
- 1. CYP2D6 in Caucasians
- 2. CYP2D6*10 in Asians
- 3. CYP2D6*17 in Africans
CYP2D6 Genetic Polymorphism
- approximately 5-10% of Caucasians are poor metabolizers, completely lacking in CYP2D6 activity due to inactivating mutations
- Asian (CYP2D6*10) and most African (CYP2D6*17) populations may have higher frequencies of LOW activity (African except for Ethiopian)
What are the consequences of being a poor metabolizer (eg. having some genetic polymorphism that affects an enzyme)?
- reduced first-pass effect
- increased oral bioavailiblity (more drug enters the circulation)
- increased plasma levels
- reduced metabolic clearance
- increased half-life
- increased drug accumulation w/ repeated doses
- reved up alternative pathway metabolism (the body has to find some way to clear drug)
- failure to activate prodrugs
- unaffected by drugs that are inhibitors of the missing enzyme
What are two classes of drugs where it is important to be aware if someone is an EXTENSIVE metabolizer (i.e. the drug doesn't get an adequate chance to work)?
- 1. birth control pills
- 2. anticonvulsants
Lopinavir & Ritonavir (Kaletra)
- a drug-drug interaction that enhances therapeutic efficacy
- lopinavir: an oral antiretroviral protease inhibitor that treats HIV/AIDS
- lopinavir's oral bioavailability is INCREASED by ritonavir, a drug that inhibits CYP3A4 (enzyme responsible for lopinavir metabolism)
- ritonavir is anti-HIV, it provides pharmacoenhancement of lopinavir absorption --> results in a 77-fold increase in lopinavir exposure which reduces pill burden
Phase I Drug Metabolism
- includes CYP450 (oxidation), alcohol & aldehyde oxidation, azo & nitro reduction, and hydrolysis
- can either make a molecule soluble enough on it's own to be excreted in the urine or soluble enough to undergo phase II metabolism
Phase II Drug Metabolism
- includes glucuronidation, acetylation, sulfate conjugation, and methylation
- after such reactions drugs & their metabolites are usually water soluble enough to LEAVE the body
Cytochrome P450 Enzymes
a major class of drug-metabolizing enzymes mainly located in the liver
What is the most important type of CYP450 enzyme?
- CYP3A (CYP3A4/5)
- it's located in the GI tract mucosa & liver, & metabolizes more than 50% of drugs currently on the market!
Nomenclature for CYP450 Enzymes
- 1st #: family (sequences with greater than or equal to 40% identity are grouped in the same family)
- 2nd letter: subfamily (sequences with greater than or equal to 60% identity are grouped in the same subfamily)
- 2nd #: the specific gene
What is the most common type of drug conjugation reaction?
- 1. lorazepam (anxiolytic)
- 2. morphine (the opioid analgesic)
- 3. AZT (antiretroviral zidovudine)
- these meds are all common substrates for glucurodination
- a major active metabolite of morphine
- the molecule responsible for much of the pain-relieving effects of morphine
- M6G is formed from morphine by the enzyme UDP-Glucuronosyltransferase-2B7 (UGT2B7)
- while most metabolites that undergo glucuronidation are soluble enough for excretion, M6G is relatively INSOLUBLE in comparison, & can accumulate to toxic levels causing kidney failure
modify the movement of some drugs from one site to another but do not alter a drug’s structure
What is the most important transporter for drug movement?
- P-glycoprotein (P-gp)
- it primarily protects the body from unfavorable foreign substances
- exhibits broad substrate specificity that tends to overlap with CYP3A4
- in the GI tract mucosa it may transport drugs back into the lumen, reducing absorption
- in the blood-brain barrier it may transport the drug back into the circulation, preventing access to the brain
Digoxin & P-gp
- as a substrate for the P-gp transporter, oral absorption of digoxin can be ENHANCED by medications that antagonize P-gp in the GI mucosa (like quinidine, an antiarrhythmic)
- alternatively, oral absorption of digoxin can be REDUCED by medications that induce P-gp (like rifampin, the antibiotic)
What is a dietary supplement that induces P-gp?
St Johns wort