Week 5, 6 - Drug Clearance, Hepatic elimination and Renal elimination Flashcards
What does elimination consist of (2 routes)
Drugs can be eliminated via 2 routes
1. Metabolism
- major sites = liver + small intestines (CYP450)
- drug can be converted into its metabolites (catalysed by metabolic enzymes)
- metabolites are polar / hydrophilic / ionised = facilitates renal elimination (urine)
- metabolites can enter systemic circulation or be excreted
- Excretion
- elimination of the unchanged drug or metabolites
- occurs in kidney (renal), liver (biliary) and lungs (pulmonary)
Difference in rate of input + rate of output (blood flow) = rate of elimination
Rate of elimination = Q (arterial conc. x venous conc.) / arterial conc.
What is clearance (Cl)
Cl = rate of drug elimination ÷ plasma conc.
- CL is constant (i.e. if 2x dose = 2x plasma conc. + 2x rate of elimination BUT Cl remains same)
- Its the apparent vol. of blood / plasma cleared of drug per unit of time
- Value of Cl depends on site of measurement i.e. blood, plasma, plasma water
- plasma is most common
- use blood clearance when calculating hepatic / renal extraction ratio
- If organ is a perfect filter Cl will = blood flow available to organ (Cl CANT exceed flow)
- Cl varies in drugs depending on the organ (if its the main eliminating organ for that drug)
CL (rate of elimination) = Renal CL + Hepatic CL
What is the clinical relevance of clearance
Helps design dosage regimen
- helps calculate loading dose + maintenance dose
Elimination rate constant = Cl ÷ V
- Half life depends on CL and V
- high V = longer half life
- high Cl = shorter half life
What is extraction ratio (E)
- When calculating ratio need to use blood CL
E value is 0-1
- E = 0 = no elimination (drug isn’t cleared / no CL)
- E = 1 = complete elimination (blood flow = blood CL)
= blood flow will affect elimination (perfusion limited)
High E = ↓ bioavailability
What is hepatic extraction ratio (EH)
Extraction ratio of liver
High EH = ↑ drug excreted = ↓ bioavailability
- less drug reaches systemic circulation
<0.3 (30%) = low extraction
- liver is not good extraction for these drugs
0.3 to 0.7 - medium extraction
>0.7 (70%) = high extraction
- liver is efficient in eliminating drug
Hepatic Elimination
Explain hepatic first-pass metabolism
Loss of drug from liver via excretion / metabolism before drug reaches systemic circulation
PROCESS
1. drug enters gut lumen
2. drug absorbed across membrane into small intestines (can undergo metabolism)
3. fraction which escapes metablolism passes through hepatic portal vein into liver
4. fraction which escapes metabolism / excretion in liver enters systemic circulation
Liver blood supply & hepatic elimination
Liver is highly perfused = drugs distribute easily
Has 2 blood supplies
- hepatic portal vein (blood from small intestine to liver) ~ 75%
- hepatic artery (oxygenated blood to liver) - 25%
↑ in hepatic blood flow = ↑ hepatic CL
Liver Routes of elimination:
1. Metabolism (into metabolites ~ CYP450 enzymes)
2. Biliary excretion (eliminated via faeces)
What 5 factors effect hepatic drug clearance
- Hepatic blood flow
- ONLY affects drugs with HIGH E (>0.7 extraction ratio)
- changes in blood flow affect CL in liver (perfusion limited) - Plasma protein binding
- ONLY for drugs with LOW E (<0.3)
- protein conc. changes due to illness e.g. cancer, stress = fraction unbound (fu) changes
- ↓ plasma protein = ↑ drug fu = ↑ CL (vice versa) - Enzyme activity
- DDIs: enzyme induction (↑ activity = ↑ CL) or inhibition (↓ CL)
- caused by co-administration of other drugs
- Genetic polymorphism = have diff. variants other than wild type (normal) i.e. reduced enzyme activity = ↓ CL - Disease status (liver cirrhosis)
- ↓ activity of hepatocytes
- ↓ activity of metabolic enzyme + drug transporters = ↓ CL for many drugs
= dose modifications required
- ↓ plasma protein as liver can’t synthesis it
- changes in hepatic blood flow + liver vol.
- GFR impairment - Transporter activity (uptake or efflux)
- changes in activity e.g. DDI, genetic polymorphism = CL ↓
- uptake by OATP1B1, metabolism by CYP450 / UGT enzymes
- efflux = biliary excretion or BCRP enzyme
- excrete unchanged drug or metabolite into bile
Can all drugs be biliary excreted
NO, need to have certain properties e.g. polar molecule or be a metabolite
Can have hepatic metabolic CL and hepatic biliary CL
What is enterohepatic recycling of drugs
- drug enters liver, metabolite is formed then is secreted into bile + reaches small intestines
- some metabolite is excreted into faeces
- some metabolite is converted back into parent molecule + reabsorbed into liver from intestines
- undergoes metabolism again
- Occurs with bile salts (= can be reused by body)
entero = intestines
hepatic = liver
What are the therapeutic consequences of enterohepatic recycling
- If drug re-enter liver instead of being excreted out = remains in systemic circulation = ↑ in drug plasma conc.
- Prolonged effects of drug = adverse events
= when drug reaches max conc. it will decline due to elimination but increase agin due to reabsorption
Renal Elimination
Why is renal excretion important for systemically acting drugs
- Its a major elimination route for many drugs + their metabolites formed in liver
- Kidneys have important renal transporter DDIs
- some drugs may inhibit transporters = ↑ plasma conc. of drug + ↓ renal CL
- can be beneficial (reduced frequency of dose) or negative - Most renal excreted drugs are excreted via urine
Explain the mechanism of renal drug excretion
- Kidneys received 20% of CO (highly perfused organs) which excrete drugs / metabolites / waste products via urine
MECHANISM:
1. Glomerulus Filtration:
- passive process that filters plasma water / blood containing unbound drug, glucose, electrolytes, small molecules etc.
- GFR = 120ml/min = 120ml is filtered every min.
- if Fu = 1 = CL rate = GFR
- GFR depends on gender, body size + age (↓ by 1% every year after 20)
- Inulin OR Creatinine can be used to determine GFR
- biomarkers for renal function + can diagnose AKI or CKD
2. Active Tubular Secretion
- when unbound drug is secreted from blood into tubular fluid to be excreted
- uptake drug from blood (secretion) via OAT1/OAT3 (anionic) and OCT2 (cation)
- elimination is via efflux transporters (MATEs) from proximal tubule
- saturable process = transporter binding sites may be full at given time
3. Tubular Reabsorption
- Substances in tubular fluid can be reabsorbed into blood + re-enter systemic circulation
- Drugs, metabolites, substances in tubule fluid that aren’t reabsorbed are excreted
CL = rate of urinary excretion / conc. plasma
