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BLOOD
ADP
ATP
+
Urate
Na
URINE
Na
-KG2-
OAT4
-KG2-
OAOAT1
ATP
MRP4
ADP
-70 mV
BLOOD
Na
URINE
ADP
ATP
+
Na
H
OC+
OCT2
Competition:
Trimethoprim or cimetidine Procainamide
Pyrimethamine Metformin
MATE1
-70 mV
BLOOD
ADP
ATP
+
Na
Na
Cys
GSH
Digoxin
OATP8
ATP
ADP
URINE
-70 mV
MDR1
(Pgp)
Gentamicin
Fluconazole
Little: 11%
Freely
MINIMAL: <2%
3 hrs
Little: <10%
Freely
EXTENSIVE: 80%
30 hrs*
*A second reason for slower elimination of fluconazol is its larger volume of distribution
(0.6 L/kg) compared to that of gentamicin (0.3 L/kg)
Li+ is freely filtered in the glomeruli, yet its renal clearance is only 10-40 ml/min, as Li+ is
largely reabsorbed in the tubules. In Li+ intoxication we can speed up the elimination of Li+ by
hemodialysis, as the hemodialysis clearance of Li+ is 70-170 ml/min.
Mechanism:
- For most drugs: diffusion
- For some -lactam antibiotics and ACE-inhibitors: PEPT-mediated
2. Biological factors:
Tubular fluid flow rate,
if high: it dilutes the drug in the tubular fluid + shortens the residence time in tubules
decreased reabsorption increased urinary excretion
Forced diuresis may be used in intoxications to increase urinary excretion of toxicants.
However, it is rarely used because of the risks of volume depletion and electrolyte imbalance.
alkalinization of urine
with NaHCO3 infusion
40
30
20
0
0
Excreted by
renal tubular secretion
Excreted by
hepatobiliary transport
COOH
H2 C
CH2
CH3
CH 3
CH3
N
H
Benzylpenicillin
(Penicillin G)
m.w. 334
N
N
Cefoperazone
m.w. 646
COOH
O
C
O
H
HO
C
H
N
H
CH3
N
CH 2 S
N
S
HN
O
C
COOH
N
H
CH2 COOH
Cl
OH
Salicyl-glycine
(Salicyluric acid)
m.w. 165
Montelukast
m.w. 586
H3C
H3C
CH3
2. Examples for
Cholephilic organic anions
Cholephilic organic cations
Endogenous compounds:
Bile acids (as taurine or glycine conjugates)
Bilirubin (as mono- and diglucuronide)
Steroid hormones (as glucuronides)
Thyroxine (as glucuronide)
MRP2 substrates may also be transported into bile by BCRP, another primary active transporter in the bile canalicular membrane of hepatocytes.
The chemical property of the glucuronide formed in the liver determines which
transporter exports it from the liver cell: MRP1 into blood, or MRP2 into bile.
After formed in the liver, chloramphenicol glucuronide (mw 498) is transported into blood via MRP1
and MRP3 and then it is excreted into urine, whereas the larger ezetimibe glucuronide (mw 583; see
elsewhere) and bilirubin diglucuronide (mw 934) are transported into the bile via MRP2.
Chloramphenicol
Chloramphenicol glucuronide
(m.w. 498)
OH
O2N
OH
UDP-GT
UDP-GA
CH CH CH2 OH
O 2N
CH CH CH2 O
NH
H 3C
CH
H
N
H3C
CH2 CH
HO
H
N
CH2
CH2
CH2
CH2
CH2
C
O
C CHCl2
OH
CH
BLOOD
URINE
HO OH
Mrp1,3
C CHCl2
NH
COO
H
N
CH
CH 3
CH
H
N
H
N
CH2
H
N
CH
UDP-GT
UDP-GA
CH3
H
N
CH2
H 3C
H 3C
CH2 CH
OOC
OH
O
O
OH
CH2
CH 2
CH2
CH2
C
O
CH 3
CH
CH3
COO
HO
HO
OH
HO
OH
Mrp2
BILE
CH2
Tl+
KFe[Fe(CN)6]
TlFe[Fe(CN)6] + K+