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Drug Disposition > Renal Elimination > Flashcards

Renal Elimination Flashcards

1
Q

Importance of renal excretion in pharmacokinetics?

A
  • makes up 32% of renal elimination in top prescribed drugs
  • many new compounds are metabolically stable
  • major elimination mechanism for many drugs e.g. metformin, acyclovir, digoxin
  • important for elimination of many metaboites formed in liver
  • evidence of clinically relevant renal transporter DDIs
  • changes in dosage regiment may be required in renal impairment, elderly, children
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2
Q

Perfusion of the kidneys?

A

20% of cardiac output

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3
Q

What regional differences occur in the kidneys?

A
  • blood and tubular fluid flows
  • transport functions and permeability to water and salts

vary throughout the different areas of the kidney/nephron

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4
Q

Mechanisms of renal drug excretion?

A

Filtration, reabsorption, active secretion, excretion

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5
Q

Equation for total renal excretion?

A

filtration - reabsorption + secretion

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6
Q

Equation for rate of excretion?

A

CLr • C plasma

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7
Q

Units of flow for excretion?

A

L/h

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8
Q

Equation for CLr using rate of filtration etc?

A

CLr = (CLrf + CLrs)(1-Fr)

CLrf is rate of filtration
CLrs is rate of secretion
Fr is fraction reabsorbed

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9
Q

What happens in golmerular filtration?

A

Only plasma water containing unbound drug is filtered - passive process

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10
Q

How to work our CLrf?

A

fraction unbound • GFR

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11
Q

What is GFR usually independent of?

A

Renal blood flow - usually constant

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12
Q

What value can renal clearance not exceed?

A

GFR

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13
Q

How is GFR determined?

A

using inulin or creatinine

not bound to plasma proteins, Fu = 1, not secreted or reabsorbed. renal clearance is therefore equal to the GFR

Creatinine is actually actively secreted and overestimates GFR, but very easy to use clinically

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14
Q

Average GFRs for a 20 year old?

A

120mL/min men
110mL/min women

1% decline per year after 20

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15
Q

Role of active tubular secretion?

A
  • Facilitates excretion, adds drug to tubular fluid
  • transporters exist for basic and acidic drugs - dissociation of plasma drug-protein complex as unbound drug is transported (equilibrium)
  • saturable process
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16
Q

Relationship between secretion and renal blood flow?

A

Secretion can occur very rapidly, so can lead to perfusion limited elimination

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17
Q

Which transporters are involved in tubular secretion?

A
  • uptake into renal cell but OAT1/3, OCT2, OATP4C1
  • efflux into urine by MRP2/4, MATEs, P-gp

ENT1/2, OAT4 uptake and efflux at both sides, URAT1, PEPT1/2 uptake from urine, OCTN1/2 uptake and efflux

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18
Q

Pairing of uptake and efflux transporters?

A

OAT1/3 uptakes anions from blood, MRP2/4 would efflux these molecuels

Cations taken up by OCT2, paired with MATEs which would efflux

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19
Q

What happens when drug accumulates in proximal tubule?

A

nephrotoxicity

can be a result of the transporters

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20
Q

What else can proximal tubule cells express?

A

Metabolising enzymes e.g. mycophenolic acid is extensively metabolised in the kidney by glucuronidation

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21
Q

Role of OAT1 transporters in the proximal tubule?

A
  • uptake of small organic anionic drugs

- substrates include adefovir, oseltamivir carboxylate, methotrexate, penicillin G

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22
Q

Role of OCT2 transporters in the proximal tubule?

A
  • transport of hydrophilic, low MW organic cations

- role in excretion of metformin, amaliplatin, pindolol

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23
Q

What can transporters be sensitive to?

A

pH - MATE sensitive to urine pH

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24
Q

Penicillin G rapidly eliminated by renal excretion - co-admin of G and probenecid led to increased concentrations of Penciliin G. Why?

A

Penicillin G is secreted by OAT1 in the kidney. Probenecid inhibits OAT1, which prevents the active secretion of penicillin G into the urine, so increased plasma conc

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25
Q

Probenecid and cidofovir DDI? Why is this actually desirable?

A
  • probenecid inihibts cidofovir uptake by OAT1
  • high concentrations of cidofovir in proximal tubule cells is nephrotoxic, so co-administration reduces the toxicity as slows the uptake
26
Q

Cimetidine and metformin DDI in the kidney?

A

Cimetidine inhibits OCT2, so renal clearance of metformin is reduced in coadministration

27
Q

Relationship between plasma drug concentration and rare of secretion?

A

Much like enzyme kinetics, gets saturated at a certain conc and rate will not increase further

28
Q

Relationship between plasma drug concnetration and rate of filtration?

A

Positive relationship consistently - not saturable

29
Q

Typical urine pH?

30
Q

Typical urine flow?

31
Q

General points about water reabsorption in the kidney?

A
  • approx 65% of golmerular filtrate is reabsorbed at proximal tubule
  • variable in segments like collecting duct in response to hormones
32
Q

How does concentration inside the tubule change along the nephron?

A

Working down through the regions, tubule becomes up to 120x more concentrated than blood (assuming no solute reabsorption) in the collecting duct

33
Q

What affects passive reabsorption of molecules in the kidney?

A
  • drug lipophilicity and degree of ionisation affect the rate and extent of reabsorption
  • unbound and uinionised form of the drug will cross the membrane, unionised form must be lipophilic enough to cross the membrane
  • urine flow
34
Q

When is CLr urine pH sensitive?

A

Weak acids - pKa 3-7.5
Weak bases - pKa 6-12
lipophilic and in unionised form

35
Q

What types of molecules are minimally reabsorbed and not pH sensitive?

A

pKa <3, strong acids as they are mostly ionised

pKa >12, strong bases as they are mostly ionised

36
Q

Effect of urine pH on elimination of weak acids?

A

CLr increases as pH increases (more reabsorption when molecule is unionised at low pH)
increased ionisation
decreased reabsorption
increased excretion

37
Q

What types of molecules are very well reabsorbed and not pH sensitive?

A

Very weak acids pKa >7.5, mostly unionised over pH range

Very weak bases, pKa <6

38
Q

Effect of urine pH on elimination of weak bases?

A

CLr increases as pH decreases - molecule becomes more ionised so less reabsorption

39
Q

What type of drug is amphetamine, and how does its CLr change with pH?

A

Weak base
pH 6.3 (normal) has urine recovery 40%
pH 5.3 has recovery 70%
pH 7.3 has recovery 3%

40
Q

Effect of urine flow on passive reabsorption in the kidney?

A

Flow dependent CLr if equilibrium is achieved between plasma and tubular fluid (urine) i.e. in substantial reabsorption

More flow will lead to more drug in urine (higher CLr)

41
Q

Effect of forced alkalined diuresis on phenobarbitone?

A

weak acid so CLr increases with pH

also urine flow dependent so increasing urine flow and increasing pH maximises rate of excretion

application: drug overdose

42
Q

Under what conditions is forced diuresis effective?

A

If renal excretion of the drug is significant under normal conditions (and the drug CLr is urine pH sensitive)

43
Q

Assumptions if CLr = Fu • GFR

A

no reabsorption or secretion

or reabsorption = secretion

44
Q

What does it mean when CLr > Fu • GFR

A

Net secretion (movement out of the blood into tubular fluid) - many acids and bases

45
Q

What does it mean when CLr < Fu • GFR

A

Net reabsorption (movement from tubular fluid into blood) - generally lipophilic molecules

46
Q

Where in the kidney is CYP3A5 located?

A

Cortex and medulla

47
Q

Where in the kidney is CYP2D6 located?

A

Cortex > medulla

highest in proximal tubule and loop of henle

48
Q

Where in the kidney is UGT1A9 located?

A

proximal tubule, distal tubule, loop of henle, collecting duct

49
Q

Where in the kidney is UGT2B7 located?

A

proximal tubule, distal tubule, loop of henle, collecting duct

50
Q

Where in the kidney are carboxylesterases located?

A

Proximal tubule, Bowman’s capsule

51
Q

Role of renal glucuronidation?

A

Important for certain drug molecules

endogenous molecules e.g. arachidonic acids, prostaglandins

52
Q

What relating to NSAIDs is linked to renal toxicity?

A

Acyl-glucuronides

53
Q

Effect on glucuroninidation enzymes as a result of kidney tumours?

A

Significant variability in expression and activity of enzymes, especially UGT1A6 and 2B7

leads to reduced renal glucuronidation in tumours

54
Q

Impact of renal disease/impairment on drug dosage regimen?

A

leads to increased plasma concentrations, risk of toxicity

55
Q

When is dose adjustment needed in renal impairment?

A
  • If the fraction excreted unchanged is >50%
  • narrow therapeutic window e.g. digoxin
  • active metabolites e.g. morphine 6-glucuronide
  • impaired metabolism e.g. polymorphic enzyme CYP2D56
56
Q

Which physiological changes occur in the kidney in CKD?

A
  • reduced CLr
  • reduced blood flow and kidney weight
  • decreased GFR
  • possible changes in tubular surface area
  • decreased tubular secretion (reduced transporter expression/activity, inhibitory effect of uremic solutes, proximal tubule cell numbers reduced)
  • reduced renal metabolism, thought to be reduced UGT
57
Q

Which physiological changes occur in the liver in CKD?

A

Reduced clearance of drugs that are not renally cleared

  • downregulation or inhibition of CYPs
  • reduced OATP activity
  • reduced UGT1A9 and 2B7
58
Q

Which physiological changes occur in the GI tract in CKD?

A
  • increased gastric emptying time (delayed)
  • increased intestinal pH
  • possible change in expression of CYPs
59
Q

Effect of CKD on albumin and haematocrit?

A

both are reduced compared to healthy subjects

60
Q

What other factors can affect protein binding in CKD?

A
  • competition for binding sites by uremic solutes

- limited data suggests elevated alpha-acid glycoprotein

Drug Disposition (11 decks)

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