Renal Elimination Flashcards
Importance of renal excretion?
- A major elimination mechanism for many drugs e.g. metformin, acyclovir, digoxin
- Important for elimination of many metabolites formed in the liver
- Important for elimination of many metabolites formed in the liver
Changes in dosage regimen may be required in:
- Patients with renal impairment
- Elderly – reduced GFR
- Children – physiological differences
Structure of kidney:
Medulla, capsule, cortex, ureter
- Perfusion of kidneys – receive 20% of cardiac output!
Distinct regional differences in:
- blood and tubular fluid flows
- transport functions and permeability to water and salts
Mechanisms of renal drug excretion:
1) Glomerular filtration
GFR = 120 ml/min
2) Reabsorption -– moves drug back to systemic circulation
3) Active secretion – also facilitate excretion (excretion = filtration - reabsorption + secretion
Rate of excretion =
CLR·C
Renal clearance=
CLR = Rate of Urinary Excretion /C plasma
Units = L/h
Higher plasma conc, higher rate of excretion
Components of Renal Clearance:
Rate of Excretion= [Rate of
Filtration + rate of secretion] x [1-fraction reabsorbed]
CLR = (CLRF + CLRS)(1- FR)
CLRF – renal filtration clearance
CLRS – renal secretion clearance
FR - fraction of filtered and secreted drug reabsorbed
Glomerular filtration is:
- A passive process, only plasma water containing unbound drug (Cu) is filtered! using passive diffusion simply following conc gradient
- Only unbound drug is going to be filtered and any small molecules will be filtered
CLRF = fu x GFR (fu = fraction unbound in plasma)
If you have highly bound drug, GFR will be fairly _____.
Low
How is GFR determined?
Determined using inulin (large molecular carbohydrate NOT insulin) or creatinine*
Good markers because (not bound to plasma proteins, fu=1; not secreted or reabsorbed)
Renal clearance (GFR) =
CLR = fu •GFR
e.g. 1 x GFR
GFR depends on:
- Body size, gender and age
- Men (20 yr) – 120 ml/min
- Women (20 yr) – 110 ml/min
GFR decreases by 1% per year after age 20
GFR marker, highly correlated with:
inulin clearance
HOWEVER: Creatinine CLR > GFR
Net CLR,sec ≈ on average 9% of CLR
Detect/ monitor/ diagnose acute kidney injury or chronic kidney disease.
Active tubular secretion facilitates:
excretion, because it adds drug to tubular fluid.
Transporters exist for basic and acidic drugs
Dissociation of plasma drug-protein complex as unbound drug is transported
- It is a Saturable process, competition (multiple drugs competing due to similar substrate specificities)
If no reabsorption occurs, all drug presented to the kidney may be excreted in the urine
Transporters and metabolic enzymes expressed in the kidney proximal tubule. Organic anion transporter (OAT1):
- Role in uptake of small organic ANIONIC drugs
- OAT1 substrates - adefovir, oseltamivir carboxylate, methotrexate, penicillin G
Transporters and metabolic enzymes expressed in the kidney proximal tubule.
Organic cation transporter (OCT2):
- Transport of hydrophilic, low molecular weight organic CATIONS
- Role in excretion of metformin, amaliplatin, pindolol
Clinical relevance of renal transporters (penicillin G)
- Penicillin G is rapidly eliminated via renal excretion (80% excreted in urine within 3 h).
- Co-administration with probenecid increases plasma concentrations of penicillin G.
- Pencillin is a substrate for OAT1
Probenecid inhbits OAT1 – so less penicillin be taken up by renal transporter therefore staying in plasma and increasing conc.
Excretion rate and plasma drug conc graph:
Excretion: carries on increasing because it is driven by filtration which isn’t saturable.
Secretion= linear relationship between plasma drug conc and excretion rate (Tm) so plateus when it reaches Tm
Filtration= Filtration process = non saturable process due to passive diffusion and simply driven by concentration gradient
Renal excretion is a NET effect of 3 processes:
1) Glomerular filtration
GFR = 120 ml/min
2) Reabsorption – important as GFR is a lot faster than urine flow
3) Active secretion
Consideration of water reabsorption. Approx. 65% of GFR ____ at proximal tubule
Reabsorbed
Variable in segments like collecting duct in response to hormones.
Passive reabsorption:
- Drug lipophilicity and degree of ionization affect the rate and extent of reabsorption
- UNBOUND and NONIONISED form of the drug crosses the membrane.
- Nonionised form needs to be lipophilic enough to be reabsorbed
Cu+ Cu0 Cur0 Cur+
Urine pH varies:
4.5 – 7.6 depending on physical activity, diet etc.
Weak acids - CLR is urine pH-sensitive if:
pKa = 3 – 7.5 and
lipophilic in nonionised form in order to be sensitive/to be reabsorbed
pKa < 3 strong acids, mostly ionised – minimal reabsorption
pKa > 7.5 very weak acids, mostly nonionised over urine pH range – more reabsorption and less renal elimination
Effect of urine pH on elimination of weak acids?
As urine pH increases, sulpha. becomes more ionized, therefore less reabsorption and more drug cleared
Increased ionization
Decreaed reabsorption
Incresed excretion
Passive reabsorption – effect of urine pH.
Weak bases - CLR is urine pH-sensitive if:
pKa = 6 – 12 and
lipophilic in nonionised form
pKa < 6 - mostly nonionised over urine pH range
pKa > 12 - mostly ionised – minimal reabsorption
Effect of urine pH on urinary excretion elimination of weak bases – e.g., amphetamine
(urine recovery = how much molecule exctreted in 24 hours)
Urine pH –> Urinary recovery
Normal 40%
Acidic 70%
Alkaline 3%
Passive reabsorption – effect of urine flow
Flow-dependent CLR occurs when drug is reabsorbed
If equilibrium is achieved – a higher urine volume means a higher amount of drug in urine and higher CLR
CLR = Rate of excretion /Cplasma
= Urine Flow x Urine conc /Cplasma
At equilibrium: Cu = Urine Conc. CLR=
CLR = fu (fraction unbound) x Urine Flow
Effect of forced alkalined diuresis – e.g., phenobarbitone
- Drug overdose- forced diuresis and altered pH may be used to increase elimination of the drug
- Only effective if renal excretion of the drug is significant under normal conditions!
Reabsorption - summary
- Passive process, dependent on drug properties
- CLR is urine pH-sensitive only for weak acids and bases
- CLR for very strong/ v. weak acids and bases is not dependent on urine pH
- If reabsorption tends to equilibrium, CLR is urine flow dependent
Identifying mechanism of renal elimination:
CLR = fu • GFR
Neither reabsorption nor secretion; or reabsorption = secretion
CLR > fu • GFR Net secretion (many acids, bases)
CLR < fu • GFR Net reabsorption(generally lipophilic molecules)
Kidney as a metabolising organ :
CYP3A5 –> Cortex and medulla
CYP2D6 –> Paediatric; adult expression possibly low; Cortex > Medulla, Highest in PT and Loop of Henle
UGT1A9–> PT, DT, LoH, CD
Carboxylesterases –>
PT, Bowman’s capsule
Changes in physiological parameters in chronic kidney disease. Kidney:
Decreased QR and kidney weight
Decreased GFR
Stages 1-5: ≥ 90 to <15 mL/min/1.73m2
Changes in tubular surface area?
Decreased tubular secretion
- decreased Transporter expression/activity
- Inhibitory effect of uremic solutes
- Decreased Proximal tubule cell number
- Decreased Renal metabolism
Changes in physiological parameters in chronic kidney disease. Liver:
- Decreased CLH for nonrenally cleared drugs
- Downregulation or inhibition of CYPs
- Decreased activity OATP (SN-38)
- Decreased UGT1A9, -2B7
Changes in physiological parameters in chronic kidney disease. GI:
- Increased Gastric emptying time
- Increased pH
- Expression of CYPs?
Other factors that may affect protein binding:
- Competition for binding sites by uremic solutes
- Limited data suggest elevated -acid glycoprotein
Impact of renal disease/impairment on drug dosage regimen:
Leads to increased plasma concentrations – risk of
toxicity:
Dose adjustment needed if:
- Fraction of drug excreted unchanged (via kidneys) is > 50%
- Narrow therapeutic window
- Active metabolites – e.g., morphine 6-glucuronide
- Impaired metabolism - e.g., polymorphic enzyme - CYP2D6
