Aa

300 mg Naproxen (N) 300 mg N + 700 mg NaHCO3 300 mg N + 1400 mg NaHCO3 300 mg N + 700 mg MgCO3 300 mg N + 700 mg MgO 300 mg N + 700 mg AI(OH)3

Figure 10.3 Mean plasma concentrations [¡Jg cm 3) of naproxen in 14 male volunteers with and without intake of sodium bicarbonate, magnesium oxide or aluminium hydroxide.

Modified from E. J. Segre, H. Sevelius and J. Varaday, N. Engl. J. Med., 291, 582 (1974).

knowledge of its site of action and the potential effect of pH changes on its excretion and biotransformation, and requires knowledge of the extent of pH changes throughout the body.

Ingestion of some antacids over a period of 24 h will increase urinary pH and hence affect renal resorption and handling of the drug. For example, administration of sodium bicarbonate with aspirin reduces blood salicylate levels by about 50%, probably owing to its increased excretion in the urine. Although high doses of alkalising agents which raise the pH of the urine will increase the renal excretion of free salicylate and result in lowering of plasma salicylate levels, in commercial buffered aspirin tablets (such as Bufferin) there is insufficient antacid to cause a change in the pH of the gastric fluids. The small amount of antacid is sufficient, however, to aid the dissolution of the acetylsalicylic acid (aspirin) (see Chapter 5) and this leads to more favourable absorption rates. 4

The importance of urinary pH

Change in the pH of urine will change the rate of urinary excretion (as represented in Fig.

10.4). When a drug is in its unionised form it will more readily diffuse from the urine to the blood. In an acidic urine, acidic drugs will diffuse back into the blood from the urine. Acidic compounds such as nitrofurantoin are excreted faster when the urinary pH is alkaline. Amfetamine, imipramine and amitrip-tyline are excreted more rapidly in acidic urine. The control of urinary pH in studies of pharmacokinetics is thus vital. It is difficult, however, to find compounds to use by the oral route for deliberate adjustment of urinary pH. Sodium bicarbonate and ammonium chloride may be used but are unpalatable. Intravenous administration of acidifying salt solutions presents one approach, especially for the forced diuresis of basic drugs in cases of poisoning.

Urinary pH can be important in determining drug toxicity more directly. A preparation containing methenamine mandelate and sul-famethizole caused turbidity in the urine of 9 out of 32 patients. The turbidity was higher in acidic urine, and was caused by precipitation of an amorphous sulfonamide derivative containing 63% of sulfamethizole. In vitro, methenamine causes the precipitation of the sulfonamide at pH values from 5 to 6. The

Blood

Renal tubular wall

— Blood Filtration of drugs and other molecules through the glomerular membrane. Plasma proteins and protein-bound drugs retained in the blood

1 Active secretion of acidic & basic drugs by the tubular cells into the tubular filtrate Return of very small water-soluble drugs and lipid-soluble drugs to the blood by simple diffusion through the cell walls. Active reabsorption of acidic and basic drugs Loss of drugs into the urine which are neither actively reabsorbed nor able to return to the blood by simple diffusion

Renal tubular wall

Renal tubular wall

Urine alkaline pH = 7.8

eabsorptio

Urine alkaline pH = 7.8

Urine acidic pH = 5.6

eabsorptio

excretion

Renal tubular wall

Urine acidic pH = 5.6

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