ACTIVE TUBULAR REABSORPTION
This is of minor importance for most therapeutic drugs. Uric
acid is reabsorbed by an active transport system which is
inhibited by uricosuric drugs, such as probenecid and
sulfinpyrazone. Lithium also undergoes active tubular reab-
sorption (hitching a ride on the proximal sodium ion transport
mechanism).
FURTHER READING
Carmichael DJS. Chapter 19.2 Handling of drugs in kidney disease.
In: AMA Davison, J Stewart Cameron, J-P Grunfeld, C Ponticelli,
C Van Ypersele, E Ritz and C Winearls (eds). Oxford textbook of clin-
icalnephrology, 3rd edn. Oxford: Oxford University Press, 2005:
2599–618.
Eraly SA, Bush KT, Sampogna RV, Bhatnagar V, Nigam SK. The mole-
cular pharmacology of organic anion transporters: from DNA to
FDA?Molecular Pharmacology2004; 65 : 479–87.
Koepsell H. Polyspecific organic cation transporters: their functions
and interactions with drugs. Trends in Pharmacological Sciences
2004; 25 : 375–81.
van Montfoort JE, Hagenbuch B, Groothuis GMM, Koepsell H,
Meier PJ, Meijer DKF. Drug uptake systems in liver and kidney.
Current Drug Metabolism2003; 4 : 185–211.ACTIVETUBULARREABSORPTION 33Key points- The kidney cannot excrete non-polar substances
efficiently, since these diffuse back into blood as the
urine is concentrated. Consequently, the kidney
excretes polar drugs and/or the polar metabolites of
non-polar compounds. - Renal impairment reduces the elimination of drugs that
depend on glomerular filtration, so the dose of drugs,
such as digoxin, must be reduced, or the dose interval
(e.g. between doses of aminoglycoside) must be
increased, to avoid toxicity. - There are specific secretory mechanisms for organic
acids and organic bases in the proximal tubules which
lead to the efficient clearance of weak acids, such as
penicillin, and weak bases, such as cimetidine.
Competition for these carriers can cause drug
interactions, although less commonly than induction or
inhibition of cytochrome P450. - Passive reabsorption limits the efficiency with which the
kidney eliminates drugs. Weak acids are best eliminated
in an alkaline urine (which favours the charged form,
A), whereas weak bases are best eliminated in an acid
urine (which favours the charged form, BH). - The urine may be deliberately alkalinized by infusing
sodium bicarbonate intravenously in the management
of overdose with weak acids such as aspirin (see
Chapter 54, to increase tubular elimination of
salicylate. - Lithium ions are actively reabsorbed in the proximal
tubule by the same system that normally reabsorbs
sodium, so salt depletion (which causes increased
proximal tubular sodium ion reabsorption) causes
lithium toxicity unless the dose of lithium is reduced.
Case history
A house officer (HO) sees a 53-year-old woman in the
Accident and Emergency Department with a six-hour his-
tory of fevers, chills, loin pain and dysuria. She looks very ill,
with a temperature of 39.5°C, blood pressure of 80/60 mmHg
and right loin tenderness. The white blood cell count is
raised at 15 000/μL, and there are numerous white cells and
rod-shaped organisms in the urine. Serum creatinine is nor-
mal at 90μmol/L. The HO wants to start treatment with
aminoglycoside antibiotic pending the availability of a bed
on the intensive care unit. Despite the normal creatinine
level, he is concerned that the dose may need to be adjusted
and calls the resident medical officer for advice.
Comment
The HO is right to be concerned. The patient is hypotensive
and will be perfusing her kidneys poorly. Serum creatinine
may be normal in rapid onset acute renal failure. It is impor-
tant to obtain an adequate peak concentration to combat
her presumed Gram-negative septicaemia. It would there-
fore be appropriate to start treatment with the normal
loading dose. This will achieve the usual peak concentra-
tion (since the volume of distribution will be similar to
that in a healthy person). However, the subsequent and
maintenance doses should not be given until urgent post-
administration blood concentrations have been obtained –
the dosing interval may be appropriately prolonged if
renal failure does indeed supervene causing reduced
aminoglycoside clearance.