A Textbook of Clinical Pharmacology and Therapeutics

32 RENAL EXCRETION OF DRUGS
the renal plasma in a single pass through the kidney (i.e. during
intravenous infusion of PAH its concentration in renal
venous blood is zero). Clearance of PAH is therefore limited
by the rate at which it is delivered to the kidney, i.e. renal
plasma flow, so PAH clearance provides a non-invasive measure
of renal plasma flow.
OCT contributes to the elimination of basic drugs (e.g.
cimetidine, amphetamines).
Each mechanism is characterized by a maximal rate of
transport for a given drug, so the process is theoretically saturable,
although this maximum is rarely reached in practice.
Because secretion of free drug occurs up a concentration gradient
from peritubular fluid into the lumen, the equilibrium
between unbound and bound drug in plasma can be disturbed,
with bound drug dissociating from protein-binding
sites. Tubular secretion can therefore eliminate drugs efficiently
even if they are highly protein bound. Competition
occurs between drugs transported via these systems. e.g.
probenecid competitively inhibits the tubular secretion of
methotrexate.
PASSIVE DISTAL TUBULAR REABSORPTION
The renal tubule behaves like a lipid barrier separating the
high drug concentration in the tubular lumen and the lower
concentration in the interstitial fluid and plasma. Reabsorption
of drug down its concentration gradient occurs by passive diffusion.
For highly lipid-soluble drugs, reabsorption is so effective
that renal clearance is virtually zero. Conversely, polar
substances, such as mannitol, are too water soluble to be
absorbed, and are eliminated virtually without reabsorption.
Tubular reabsorption is influenced by urine flow rate.
Diuresis increases the renal clearance of drugs that are passively
reabsorbed, since the concentration gradient is reduced
(Figure 6.2). Diuresis may be induced deliberately in order to
Low urine
flow rate
D
D in urine
High urine
flow rate
D
D in urine
Indicates passive reabsorption in distal tubule
Figure 6.2: Effect of diuresis (urine flow rate) on renal clearance
of a drug (D) passively reabsorbed in the distal tubule.
increase drug elimination during treatment of overdose
(Chapter 54).
Reabsorption of drugs that are weak acids (AH) or bases
(B) depends upon the pH of the tubular fluid, because this
determines the fraction of acid or base in the charged, polar
form and the fraction in the uncharged lipid-soluble form. For
acidic drugs, the more alkaline the urine, the greater the renal
clearance, and vice versa for basic drugs, since:
and
AH A��H� B�H BH
� �
.
Thus high pH favours A � , the charged form of the weak
acid which remains in the tubular fluid and is excreted in the
urine, while low pH favours BH � , the charged form of the
base (Figure 6.3). This is utilized in treating overdose with
aspirin (a weak acid) by alkalinization of the urine, thereby
accelerating urinary elimination of salicylate (Chapter 54).
The extent to which urinary pH affects renal excretion of
weak acids and bases depends quantitatively upon the pK a of
the drug. The critical range of pK a values for pH-dependent
excretion is about 3.0–6.5 for acids and 7.5–10.5 for bases.
Urinary pH may also influence the fraction of the total dose
which is excreted unchanged. About 57% of a dose of amphetamine
is excreted unchanged (i.e. as parent drug, rather than
as a metabolite) in acid urine (pH 4.5–5.6), compared to about
7% in subjects with alkaline urine (pH 7.1–8.0). Administration
of amphetamines with sodium bicarbonate has been used illicitly
by athletes to enhance the pharmacological effects of the
drug on performance, as well as to make its detection by urinary
screening tests more difficult.
Low pH High pH
AH A �
BH � B
BH �
A �
in urine
AH A �
BH � B
A �
BH �
in urine
Indicates passive reabsorption in distal tubule
Figure 6.3: Effects of urine pH on renal clearance of a weak acid
(AH) and a weak base (B).