Elementary Drug Metabolism

Question 1

Four processes influencing drug disposition?

Answer 1

Absorption
Distribution

Metabolism
Excretion
…together make up elimination

Question 2

How do most drugs leave the body?

Answer 2

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

Question 3

What are drugs in relation to the body?

Answer 3

Xenobiotics - not endogenous compounds

Question 4

How does drug metabolism act on drugs?

Answer 4

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)

Question 5

Main organ of drug metabolism?

Answer 5

Liver

Also, GI tract, lungs and plasma have some activity

Question 6

Two, sequential phases of drug metabolism?

Answer 6

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

Question 7

Aspirin undergoing 2 phases of drug metabolism?

Answer 7

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)

Question 8

Exceptions to 2 phases of metabolism?

Answer 8

If drug is already chemically reactive

Other drugs are highly polar initially and proceed straight to phase 2 metabolism

Question 9

What is the Cytochrome P450 (CYP) family of monooxygenases?

Answer 9

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

Question 10

Main gene families in human liver?

Answer 10

CYP1, CYP2, CYP3

Question 11

Important CYP?

Answer 11

CYP3A4 - responsible for metabolism of >50% of all prescribed drugs

Question 12

Describe the Monooxygenase P450 cycle?

Answer 12

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

Question 13

Describe phase 2 reactions?

Answer 13

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

Question 14

What is glucoronidation?

Answer 14

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

Question 15

How does glucoronidation occur?

Answer 15

UDP-GLUCORONYL TRANSFERASE transfers glucoronic acid to electron-rich atoms of the substrate

UDP acts to donate its glucoronyl group

Question 16

Three processes in renal excretion of drugs and their metabolites?

Answer 16

1. Glomerular filtration - plasma is filtered at each nephron in glomerulus (tuft of capillaries surrounded by Bowman’s capsule)
2. Active tubular secretion - transport processes present in kidney proximal tubules
3. Passive reabsorption by diffusion across the tubular epithelium at the distal tubules (if drug is lipophyllic)

Question 17

On what drugs does glomerular filtration occur?

Answer 17

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

Question 18

What drugs can enter the filtrate?

Answer 18

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

Question 19

Equation for clearance by filtration?

Answer 19

Clfil = GFR x fraction of drug unbound in plasma (fup)

GFR = Glomerular Filtration Rate (normally 120 ml min-1)

Question 20

How does tubular secretion of drugs work?

Answer 20

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

Question 21

How does tubular secretion secrete drugs that are highly protein-bound?

Answer 21

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

Question 22

Most effective mechanism of drug elimination by kidney?

Answer 22

Potentially, excretion by tubular secretion

Question 23

Drugs and substances transported by OAT?

Answer 23

Acetazolamide, frusemide, thiazides (diuretic agent)

Question 24

Drugs and substances transported by OCT?

Answer 24

Amilorides
Triamterene (diuretic agent with selective action on kidney)

Question 25

Competition with transporter systems?

Answer 25

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

Question 26

Factors influencing tubular reabsorption?

Answer 26

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