Elementary Drug Metabolism Flashcards
Four processes influencing drug disposition?
Absorption
Distribution
Metabolism
Excretion
…together make up elimination
How do most drugs leave the body?
In the URINE, either UNCHANGED (e.g: highly charged) compounds or, more usually, chemically transformed compounds rendered MORE POLAR by metabolism
Excretion via BILE is sometime significant and others inc. sweat, milk
What are drugs in relation to the body?
Xenobiotics - not endogenous compounds
How does drug metabolism act on drugs?
Convert parent drugs to MORE POLAR metabolites that are NOT READILY REABSORBED by the kidneys (from renal tubules), facilitating excretion
Be converted from INACTIVE prodrugs to ACTIVE compounds, e.g: enalapril to enalaprilat, or GAIN ACTIVITY, e.g: codeine to morphine via O-dealkylation
Have UNCHANGED activity, e.g: diazepam to nordiazepam
Possess a different type, or spectrum, of action, e.g: aspirin (anti-inflammatory and anti-platelet) vs its metabolite salicylic acid (anti-inflammatory, no anti-platelet activity)
Main organ of drug metabolism?
Liver
Also, GI tract, lungs and plasma have some activity
Two, sequential phases of drug metabolism?
Phase I - Oxidation, reduction, hydrolysis reactions make the drug more polar
A chemically reactive drug (a “handle”) is added, permitting conjugation (FUNCTIONALISATION)
Phase 2 - Conjugation:
Adds an endogenous compound, increasing polarity, e.g: with glucotonyl, sulphate, methyl, acetyl, glycyl or glucathione groups
Some drugs are excreted unchanged
Aspirin undergoing 2 phases of drug metabolism?
Phase 1 is catabolic generally:
Aspirin to salicylic acid (derivative)
Phase 2 is anabolic generally:
Salicylic acid to glucoronide (conjugate added - very polar so ready for excretion)
Exceptions to 2 phases of metabolism?
If drug is already chemically reactive
Other drugs are highly polar initially and proceed straight to phase 2 metabolism
What is the Cytochrome P450 (CYP) family of monooxygenases?
Haem proteins (contain iron) located in the ER of liver hepatocytes, and elsewhere, mediating OXIDATION REACTIONS (PHASE 1)
Comprise a superfamily classified as CYP followed bya defining set of number and letters (gene family, then gene sub family and then individual gene)
Have distinct but overlapping substrate specificities
Main gene families in human liver?
CYP1, CYP2, CYP3
Important CYP?
CYP3A4 - responsible for metabolism of >50% of all prescribed drugs
Describe the Monooxygenase P450 cycle?
Drug enters cycle as DRUG SUBSTRATE (DH - drug with a hydrogen)
Molecular oxygen (O2) provides 2 atoms of oxygen: One atom of oxygen is added to the drug to yield the hydroxyl product, which leaves the cycle Second oxygen atom combines with protons to form H2O
The cytochrome will return to its ferric state, at this point
Describe phase 2 reactions?
Largely occur in liver and usually result in INACTIVE PRODUCTS
Involves conjugation of chemically reactive groups, e.g: hydroxyl, thiol, or amino with glucoronyl, sulphate, methyl or acetyl groups
What is glucoronidation?
Phase 2 reaction that is common and involves transfer of glucoronic acid to electron-rich atoms of the substrate (N, O or S forming amide, ester, or thiol bonds)
Many endogenous substances undergo glucoronidation, e.g: bilirubin, adrenal corticosteroids
How does glucoronidation occur?
UDP-GLUCORONYL TRANSFERASE transfers glucoronic acid to electron-rich atoms of the substrate
UDP acts to donate its glucoronyl group
Three processes in renal excretion of drugs and their metabolites?
- Glomerular filtration - plasma is filtered at each nephron in glomerulus (tuft of capillaries surrounded by Bowman’s capsule)
- Active tubular secretion - transport processes present in kidney proximal tubules
- Passive reabsorption by diffusion across the tubular epithelium at the distal tubules (if drug is lipophyllic)
On what drugs does glomerular filtration occur?
Occurs freely for drugs with a molecular weight of less than 20, 000 (very few exceed this), provided they are not bound to large plasma proteins (which are not filtered)
Drug charge is unimportant
What drugs can enter the filtrate?
Many drugs bind reversibly to large plasma proteins (e.g. albumin and α1-acid glycoprotein) and exist in blood in an equilibrium between unbound and protein-bound forms
Only UNBOUND molecules can enter filtrate, via glomerular filtration
So, if a drug binds to plasma protein, its conc. in glomerular filtrate is less that total Cp
Equation for clearance by filtration?
Clfil = GFR x fraction of drug unbound in plasma (fup)
GFR = Glomerular Filtration Rate (normally 120 ml min-1)
How does tubular secretion of drugs work?
Can concentrate drugs in tubular fluid against an electrochemical gradient
Epithelial cells of the proximal tubule contain 2, independent, transporter systems that ACTIVELY secrete drugs into the lumen of the nephron
Organic Anion Transporter (OAT) - handles ACIDIC drugs, endogenous acids, e.g: uric acid, and the marker for renal plasma flow, i.e: para-aminohippurin acid (PAH)
Organic Cation Transporter (OCT) - handles basic drugs
How does tubular secretion secrete drugs that are highly protein-bound?
Free and bound forms exist in EQUILIBRIUM (50% free and 50% bound)
Free drug conc. reduced by secretion - establishes new equilibrium between bound and free drug
Free drug conc. further reduced by secretion – causes additional drug to dissociate from protein and this is secreted
Most effective mechanism of drug elimination by kidney?
Potentially, excretion by tubular secretion
Drugs and substances transported by OAT?
Acetazolamide, frusemide, thiazides (diuretic agent)
Drugs and substances transported by OCT?
Amilorides Triamterene (diuretic agent with selective action on kidney)
Competition with transporter systems?
Tubular secretion is a saturable process, each carrier has a transport maximum (Tm) for a part. drug
Drugs and substances sharing the same transporter system may compete with each other for secretion leading to interactions, e.g:
Probenecid has been used to retard the excretion of penicillins
Frusemide and thiazides may retard the excretion of uric acid and precipitate gout
Factors influencing tubular reabsorption?
Lipid solubility – drugs with high lipid solubility will be extensively reabsorbed and excreted slowly
Polarity – highly polar drugs will be excreted without reabsorption
Urinary flow rate – diuresis decreases reabsorption
Urinary pH – the degree of ionisation of weak acids and bases can strongly influence their reabsorption:
Alkaline pH - increases excretion of acids (urinary alkalisation can be used to accelerate aspirin excretionin cases of overdose)
Acidic pH - increases excretion of bases
