Drug Excretion Flashcards
Drug metabolism
chemical transformation of a drug
into one or more products within the body
Drug excretion refers
solely to the physical processes that lead to the irreversible removal of a drug and its metabolites from the body
Drug metabolism and drug excretion =
Drug elimination
Drug elimination is
The removal of drug from the body through metabolic and/or excretory processes
A.D.M.E
Absorption
Distribution
Metabolism
Excretion
Drug elimination made up of
Drug metabolism (75%) mediated by CYP450
and
Drug excretion
Routes of Drug excretion
urine (kidneys)
faeces (bile)
breast milk - minor route and can pass from mother to baby
expired air (lungs)
hair
skin/sweat
Do hydrophilic drugs require hepatic metabolism
No
Factors that influence renal excretion (7)
- Molecular weight and size
- Drug concentration
- Urine pH
- Plasma protein binding
- Rena; blood flow
- Impaired renal Function
- Transporters
What types of drugs reduce renal function
non-steroidal and anti-immflamible drugs
3 types of renal excretion
Glomerular Filtration
Passive reabsorption
Active tubular Secretion
Glomerular Filtration
20% of renal plasma flow is filtered thru glomerular capillaries (GFR=120mL/min and declines due to aging or disease)
- Only small and free drugs can pass thru glomerular capillaries into the filtrate
-altered plasma protein binding can influence filtration
What is can influence glomerular filtration
-altered plasma protein binding can influence filtration
GFR
Glomerular filtration rate
Fu fraction of drugs ___ in plamsa
Unbound
Fu Equation
Cl(gf) = fu * GFR
renal clearance by glomerular filtration
Estimated GFR (eGFR) - measure blood____ level
creatinine
Impaired renal function →
blood creatinine level ↑
[2]Passive reabsorption
- most filtrate returns to circulation through peritubular capillaries (1% becomes urine)
- Water reabsorption → drug concentration ↑ in the filtrate
- passive diffusion - small, lipophilic and unionised drugs
- transporter-mediated (e.g., PEPT2 and peptide-like drugs)
- urine pH affects drug ionisation and reabsorption
Peritubular capillaries
Peritubular capillaries are tiny blood vessels in your kidneys. They filter waste from your blood so the waste can leave your body through urine (pee). Peritubular capillaries also reabsorb nutrients your body needs to work properly, such as minerals.
Urine pH affects drug ionisation and___
reabsorption
Salicylate overdose facts
- Aspirin or methyl salicylic acid (e.g., infant teething gels)
- i.v. sodium bicarbonate (an alkalinising agent) injected intravenously.
- ↑ urine pH
- ↑ salicylic acid ionisation
- ↓ reabsorption of salicylate
Salicylate overdose explain
Sodium bicarbonate (administered intravenously) increases the pH of the blood. By raising the blood pH, sodium bicarbonate facilitates the ionisation of salicylic acid, converting it into a less toxic form, salicylate ions.
By increasing urine pH, sodium bicarbonate facilitates the conversion of salicylic acid into its ionized form, which is more readily excreted in urine.
Only what type of molecules can cross cell membranes (Ion ro Union)
Unionised
Active tubular secretion
Peritubular capillaries→ the tubular lumen
- occurs predominantly in proximal tubules
- mediated by transporters
Basolateral membrane and its transporters
the cell membrane which is oriented away from the lumen of the tubule
Solute carrier (SLC) transporters
liver-specific OATP1B1/1B3 - uptake of drugs and metabolites into hepatocytes
Apical membrane and its transporters
cell membrane which is oriented towards the lumen
ATP-binding cassette (ABC) transporters
efflux transporters - eliminate large and polar
molecules into bile
Lumen
The lumen is the space within the body’s tracts, tubes, cavities, and cells
solute carrier (SLC) transporters
- SLC22A6 - OAT1 (organic anion transporter 1)
- SLC22A8 - OAT3 (organic anion transporter 3)
ATP-binding cassette (ABC) transporters
- ABCB1 - MDR1 (multidrug resistance protein 1) or P-gp (P-glycoprotein)
- ABCC2 - MRP2 (multidrug resistance-associated protein 2)
- ABCG2- BCRP (breast cancer resistance protein)
MDR1
- large lipophilic cationic compounds
- neutral compounds
multidrug resistance protein 1
Transporter-mediated active secretion (basolateral membrane)
OAT1 and OAT3
* overlapping substrate specificity
Transporter-mediated active secretion (OAT1/3-mediated drug excretion)
e.g., cephalexin (a drug of the cephalosporin class)
- mostly excreted unchanged via urine
- glomerular filtration and active tubular secretion
- drug-drug interaction: probenecid* (an OAT1/OAT3
inhibitor; pharmacokinetic enhancer) co-administration
- Cmax
- AUC
Hepatobiliary excretion
hepatocytes produce and secrete bile
- stored in the gallbladder
- drained into bile duct then duodenum
drug excreted into bile
- glucuronides are concentrated in bile
drug metabolising enzymes produce ___ ____
conjugated metabolites
Basolateral membrane transporters:
e.g., liver-specific OATP1B1/1B3 - uptake of
drugs and metabolites into hepatocytes
Apical membrane transporters:
efflux transporters - eliminate large and polar molecules into bile
Enterohepatic recirculation
Lipophilic drugs (e.g., morphine) undergo absorption
↓
hepatic metabolism
↓
conjugates excreted into bile
↓
glucuronides in the GI tract
[hydrolysed by ß-glucuronidase
(expressed by GI bacteria)]
↓
generate unconjugated drug
↓
Back to Lipophilic drugs (e.g., morphine) undergo absorption
Enterohepatic recirculation Morphine
hydrolysed by ß-glucuronidase
(expressed by GI bacteria)
↓
Morphine back to parent drug
↓
reabsorbed to systemic circulation
↓
Prolonged effects of morphine and long half-life
Breast milk as a minor route of drug excretion
Most drugs enter breast milk via passive diffusion
- can be important for lipophilic and basic drugs (breast milk is slightly acidic)
[Slides]
Individual variation in drug response definition
individual variation in drug response refers to differences in response between individuals to the same
dose of a drug
Individual variation in drug response: intrinsic factors
genetics, age, sex, disease status or physiological conditions such as pregnancy
Individual variation in drug response: extrinsic factors
concomitant medications, diet and exposure to chemicals and other environmental causes
single nucleotide polymorphism (SNP)
- e.g., drug metabolising enzymes
- common and clinically important
- CYP SNPs
-CYP2D6 is most polymorphic
Drug clearance definition
Drug clearance refers to the efficiency of drug elimination, defined as the ratio of the elimination rate (e.g., mg∙h-1) to the concentration of drug in plasma
(e.g., mg∙L-1)
Drug clearance
- the volume of plasma that would be completely cleared of drug per unit time (e.g., L∙h-1)
- total body clearance = hepatic clearance + renal clearance + clearance by other routes OR
- clearance by a specific organ;
renal clearance = glomerular filtration + active secretion - reabsorption
fe- the fraction of administered drug
excreted ____ in the urine
unchanged
Drug clearence
dose adjustment due to impaired renal or
hepatic functions
- renal impairment - eGFR
- hepatic impairment - Child-Pugh score
Hepatic clearance influence fe
low fe
lots of hepatic metabolism and metabolites are excretede
renal clearance influence fe
high fe
little or no hepatic metabolism and the parent drug is eexcreted
Determine total body clearance
Slides
Drug bioavailability definition
Drug bioavailability (F) is the fraction of administered dose of the parent drug that reaches the systemic circulation
If a drug is administered intravenously what is the bioavailability of the drug in a fraction or %
1 or 100%
Drug bioavailability
- intravenously administered drug bypasses absorption and first-pass metabolism - F = ?
- drug administered by other routes - F is between 0 (or 0%) and 1 (or 100%)
Drug bioavailability Equations on slides
Drug elimination last slide
Probenecid
- (an OAT1/OAT3
inhibitor; pharmacokinetic enhancer) co-administration. Will increase: - Cmax
- AUC
