Drug Metabolism & Elimination

Question 1

what is metabolism?

Answer 1

the removal of lipid-soluble drug molecules to prevent reabsorption but the kidneys

Question 2

how is metabolism achieved?

Answer 2

by converting drugs into water soluble molecules in the liver, but cam also occur in the plasma, lungs and intestinal epithelial

Question 3

what is excretion?

Answer 3

the removal of drugs/metabolites from the body in urine , bile/faeces, sweat, tears and saliva

Question 4

what is clearance?

Answer 4

the volume of plasma cleared of drug per unit of time

Plasma CL = hepatic CL + renal CL

Question 5

what is the importance of drug metabolism and excretion?

Answer 5

• for dosage issue: CL determines amount of drug available at site of action and determines time taken for drug to reach steady state levels
• for safety issues: metabolism produces new chemical entities that may have its own effects
• knowledge can iAd design of future drugs
• drug metabolites measures in substance abuse tests

Question 6

what are the main concepts of metabolism?

Answer 6

• drug removal/metabolism occurs immediately
• most undergo metabolism prior to removal
• loss/reduced biological activity
• some drugs are ‘activated’ by metabolic reactions
• somedrugs are eliminated unchanged
• some metabolites are toxic

Question 7

what is the first stage of metabolism?

Answer 7

• introduction of chemically reactive groups
• main process is oxidation in the liver
• the addition of 02 molecule onto C, N, S molecule on the drug
• carried out my cytochrome P450 enzyme and its iso forms
• the other molecule of O (from O2) is sued for hydrolysis

Question 8

what is the second stage of metabolism?

Answer 8

• increasing H20 solubility of drug for excretion
• P1 products are conjugated w endogenous substances through production of stable covalent bonds

-eg: glucuronidation and sulfate conjugation

Question 9

what is different about paracetamol metabolism?

Answer 9

-PCM is more readily metabolised by P2 and only goes through P1 if the metabolites and enzymes of P2 are fully saturated

Question 10

how are drugs excreted in the kidney?

Answer 10

1) glomerulus filtration: filters out molecules which are less than 20kDa and the amount secreted is dependant on the level of drug bound to plasma membranes
2) reabsorption: as molecules pass through tubules, the [drug] increases which creates a gradient which is why drugs need to be water soluble
3) tubular secretion: acid/base molecule carriers transporting molecules into tubular fluid so there is a decrease in levels of unbound drug in plasma

Question 11

how is excretion measured?

Answer 11

excretion = filtration - reabsorption + secretion

Question 12

what is renal CL?

Answer 12

the volume of plasma cleared of drug per unit of time through one pass of the kidney

Question 13

what factors affect drug metabolism?

Answer 13

• age: cytochrome p450 activity decreases in elderly, GFR decreases and fat % increases the older you get
• genetics: 45% of europeans, 80-90% of asians have fast acetylators which increase metabolism
• drug metabolising enzymes: induced/inhibited by other drugs and lifestyle factors
• disease: live and renal disease impairs metabolism and pharmacokinetics

Question 14

why is [drug] monitored?

Answer 14

• for drugs that have a narrow therapeutic index
• to individualise therapy
• to confirm adherence of therapy
• to diagnose toxicity
• to determine presence of other drugs before starting therapy
• post market surveillance to detect drug-to-drug interactions