A Textbook of Clinical Pharmacology and Therapeutics

32 RENAL EXCRETION OF DRUGS

the renal plasma in a single pass through the kidney (i.e. dur-
ing 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 meas-
ure 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 sat-
urable, although this maximum is rarely reached in practice.
Because secretion of free drug occurs up a concentration gra-
dient from peritubular fluid into the lumen, the equilibrium
between unbound and bound drug in plasma can be dis-
turbed, with bound drug dissociating from protein-binding
sites. Tubular secretion can therefore eliminate drugs effi-
ciently 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 dif-
fusion. For highly lipid-soluble drugs, reabsorption is so effec-
tive 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 pas-
sively reabsorbed, since the concentration gradient is reduced
(Figure 6.2). Diuresis may be induced deliberately in order to

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

.

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 pKaof

the drug. The critical range of pKavalues 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 amphet-

amine 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 illic-

itly by athletes to enhance the pharmacological effects of the

drug on performance, as well as to make its detection by uri-

nary screening tests more difficult.

BH BH

AH AH

Low urine

flow rate

High urine

flow rate

D

D in urine

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.

Low pH High pH

BH

A in urine

Indicates passive reabsorption in distal tubule

AH A

BH B

AH A

BH B

A

BH in urine

Figure 6.3: Effects of urine pH on renal clearance of a weak acid

(AH) and a weak base (B).