Transcript protein binding

PHARMACOKINETICS IN CKD
R Vanholder
University Hospital, Gent,
Belgium
© 2008 Universitair Ziekenhuis Gent
MECHANISMS
OAT: organic acid transporter
P-gp: p-glycoprotein
CYP: cytochrome P
MRP: multidrugresistance
associated protein
BSEP: bile salt export pump
© 2008 Universitair Ziekenhuis Gent
Naud et al, J Clin Pharmacol, 52: 10S-22S; 2012
2
2
CONTRIBUTORS TO PHARMACOKINETICS IN CKD
Renal clearance
Glomerulus
Tubulus
Metabolism
Enterocyte
Hepatocyte
Excretion in intestine
Direct
Biliary
Protein binding
Distribution volume
Disturbed
© 2008 Universitair
Ziekenhuis Gentgastro-intestinal motility and uptake
3
3
CONTRIBUTORS TO PHARMACOKINETICS IN CKD
Renal clearance
Glomerulus
Tubulus
Metabolism
Enterocyte
Hepatocyte
VIRTUALLY ALL THESE FACTORS
INCREASE BIOAVAILABILITY
Excretion in intestine
Direct
Biliary
Protein binding
Distribution volume
Disturbed
© 2008 Universitair
Ziekenhuis Gentgastro-intestinal motility
4
4
RENAL CLEARANCE
© 2008 Universitair Ziekenhuis Gent
© 2008 Universitair Ziekenhuis Gent
6
6
drug
© 2008 Universitair Ziekenhuis Gent
7
7
© 2008 Universitair Ziekenhuis Gent
8
8
ORGANIC ANION TRANSPORTERS
© 2008 Universitair Ziekenhuis Gent
9
9
OAT ACTIVITY IS DEPRESSED IN KIDNEY FAILURE
© 2008 Universitair Ziekenhuis Gent
Takeuchi, KI, 60: 1058-1068; 2001
10
10
UREMIC TOXINS INHIBIT OATs
© 2008 Universitair Ziekenhuis Gent
Wang and Sweet, Biochem Pharmacol, 84: 1088-1095; 2012
11
11
NON-RENAL CLEARANCE
© 2008 Universitair Ziekenhuis Gent
METABOLIC ACTIVITY CYPs IS DECREASED IN
CKD
© 2008 Universitair Ziekenhuis Gent
Leblond at al, JASN, 13: 1579–1585; 2002
13
13
PROTEIN BINDING
© 2008 Universitair Ziekenhuis Gent
PROTEIN BINDING
CKD patients have low serum albumin due to inflammation, fluid
overload, malnutrition and urinary protein losses
In CKD the structure of albumin is modified
In CKD many drugs and protein bound toxins compete for protein
binding sites
All these elements tend to decrease drug protein binding, to
increase their free fraction, and to increase their activity (toxicity)
This effect is partly compensated: increased metabolism and
redistribution
© 2008 Universitair Ziekenhuis Gent
15
15
IMPORTANCE OF PROTEIN BINDING
© 2008 Universitair Ziekenhuis Gent
Vanholder et al, KI, 33: 996-1004; 1989
16
16
IMPORTANCE OF PROTEIN BINDING
© 2008 Universitair Ziekenhuis Gent
Vanholder et al, KI, 33: 996-1004; 1989
17
17
OTHER COMPETITORS
Indoxyl sulfate
Indole-acetic acid
P-cresylsulfate
…
© 2008 Universitair Ziekenhuis Gent
18
18
PRACTICAL CONSEQUENCES
© 2008 Universitair Ziekenhuis Gent
19
19
PRACTICAL CONSEQUENCES
© 2008 Universitair Ziekenhuis Gent
20
20
PRACTICAL CONSEQUENCES
© 2008 Universitair Ziekenhuis Gent
21
21
DISTRIBUTION VOLUME
© 2008 Universitair Ziekenhuis Gent
DISTRIBUTION VOLUME
Dose X0
IV
Vd C0
© 2008 Universitair Ziekenhuis Gent
23
23
DECREASE DITRIBUTION VOLUME IN AKI
INCREASES DIGOXIN CONCENTRATION
Nephron. 1984;37(3):190-4.
Rising serum digoxin without further dosage in acute renal failure.
Gault MH, Gallway B, Fine A, Vasdev S.
Abstract
A 73-year-old man was given a total of 1 mg of digoxin intravenously over 3 days, close to the
time that he developed acute renal failure with oligo-anuria. He received no cardiac glycosides
before or after this 3-day period. 2 days after the last dose, the serum digoxin concentration
(SDC) was 2.9 ng/ml, yet a peak value of 4.2 ng/ml was reached only 11 days later. The SDC
remained above 2 ng/ml for another week, until urine output began to increase appreciably. As
renal function improved, the SDC gradually fell to become undetectable 32 days after the last
dose. Values for apparent volume of distribution calculated from the total dose, and also
determined after injection of tritiated digoxin, suggest that the rise in SDC in the absence of
additional doses was due in large part to a decrease in the apparent volume of distribution.
Dosage and parameters of toxicity should be carefully monitored in patients receiving digoxin
who develop acute renal failure.
© 2008 Universitair Ziekenhuis Gent
24
24
INTESTINAL ABSORPTION
© 2008 Universitair Ziekenhuis Gent
INTESTINAL MOBILITY IS DECREASED IN
DIABETES
© 2008 Universitair Ziekenhuis Gent
Rana et al, Diab Tech Ther, 13: 1115-1120; 2011
26
26
INTESTINAL MOBILITY IS DECREASED IN CKD
© 2008 Universitair Ziekenhuis Gent
Strid et al, Digestion, 13: 129-137; 2003
27
27
MANY DIFFERENT EFFECTS
Decreased intestinal motility
Slowing down peak concntration, no change in bioavailability
Decreased gastric acidity
Due to uremia (ammonia), drugs (antacids, H2-antagonists)
Reduction bioavailability
GI edema
Cirrhosis
Cardiac failure
Reduction absorption: bioavailability furosemide from 50  10%
Sorbents
Sevelamer
All together, most elements reduce bioavailability
© 2008 Universitair Ziekenhuis Gent
28
28
ABSORPTION OF MYCOPHENOLATE MOFETYL BY
SEVELAMER
© 2008 Universitair Ziekenhuis Gent
Pieper et al, NDT, 19: 2630-2633; 2004
29
29
THE EFFECT OF DIALYSIS
© 2008 Universitair Ziekenhuis Gent
EFFECTS OF DIALYSIS ON DRUG KINETICS
One may accept that dialysis almost always decreases drug
bioavailability and at best keeps it unmodified
Drug administration best occurs after the dialysis session
The only exception are drugs that are difficult to remove by dialysis
and of which peak concentration is more important than trough
(e.g. aminoglycosides)
© 2008 Universitair Ziekenhuis Gent
31
31
EXAMPLE: MEROPENEM
5,0
Healthy
LFHD - RRF10
LFHD - RRF0
HFHD - RRF0
4,5
Concentration (mg/L)
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
2400
2450
2500
2550
2600
2650
2700
2750
2800
2850
2900
2950
time (min)
© 2008 Universitair Ziekenhuis Gent
32
32
HEMODIALYSIS RESTORES ACTIVITY OF CYP3A4
© 2008 Universitair Ziekenhuis Gent
Michaud et al, J Pharmacol Sci, 108: 157-163; 2008
33
33
CONCLUSIONS
The impact of renal failure on the many aspects of drug
pharmacokinetics is hard to predict in detail
The net effect of all influening factors is to increase bioavailability
If possible, drug treatment should be monitored by considering
plasma concentrations
© 2008 Universitair Ziekenhuis Gent
34
34