Sulfonamide drugs secretion

Source Cooke M, Davenport HW, Goodman LS. The secretion of sulfonamide drugs in gastric juice. Yale J Biol Med 14 17, 1941. 

I injected 10 ml of a solution containing 100 mg of the sodium salt of a sulfonamide drug into a dog whose blood volume I had measured with T-1824, drew samples at intervals, and measured the concentration in the samples. Sufanilamide and sulfapyridine disappeared from the blood too rapidly for me to determine ka accurately, but good estimates were obtained for the other three drugs. Table 1-6 shows that there was a reasonable agreement between observed and predicted concentration ratios at several rates of secretion. 

I sent the paper for publication within a week of obtaining the last datum. I knew the analysis of the mechanism of secretion of sulfonamide drugs had little importance in itself, but I was pleased to have pulled the physiological rabbit out of the physicochemical hat. 

These agents act in the distal portion of the distal tubule and the proximal part of the collecting ducts where Na is reabsorbed in exchange for K or H. Their diuretic effectiveness is relatively minor. In contrast to sulfonamide diuretics (p. 162), there is no increase in K secretion rather, there is a risk of hyperkalemia. These drugs are suitable for oral administration. 

Acetazolamide is an aromatic sulfonamide used as a carbonic anhydrase inhibitor. It facilitates production of alkahne urine with an elevated biocarbonate, sodium, and potassium ion concentrations. By inhibiting carbonic anhydrase, the drug suppresses reabsorption of sodium ions in exchange for hydrogen ions, increases reflux of bicarbonate and sodium ions and reduces reflux of chloride ions. During this process, chloride ions are kept in the kidneys to cover of insufficiency of bicarbonate ions, and for keeping an ion balance. Electrolytic contents of fluid secreted by the kidneys in patients taking carbonic anhydrase inhibitors are characterized by elevated levels of sodium, potassium, and bicarbonate ions and a moderate increase in water level. Urine becomes basic, and the concentration of bicarbonate in the plasma is reduced. 

Probenecid can impair the renal active secretion of a variety of acidic compounds, including sulfinpyrazone, sulfonylureas, indomethacin, penicillin, sulfonamides, and 17-ketosteroids. If these agents are to be given concomitantly with probenecid, their dosage should be modified appropriately. Salicylates interfere with the clinical effects of both sulfinpyrazone and probenecid and should be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distribution and hepatic metabolism of a number of drugs. 

Anorexia, nausea, and vomiting occur in 1—2% of persons receiving sulfonamides. The administration of sulfonamides to newborn infants, especially if premature, may lead to the displacement of bilirubin from albumin, potentially causing kemicterus. Sulfonamides should not be given to pregnant women near term because these drugs cross the placenta and are secreted in milk. 

Readily cross cell membranes generally moderate to good absorption from GIT but species-dependent effective concentrations achieved in intra- and transcellular as well as extracellular fluids except for poor penetration of sulfonamides into intracellular fluid due to acidic environment ability to penetrate into CSF and ocular fluids depends on plasma protein binding (e.g., most sulfonamides and diaminopyrimidines penetrate well) weak acids are ion-trapped in fluids alkaline relative to plasma, such as herbivore urine weak bases are ion-trapped in fluids acidic relative to plasma (e.g., prostatic fluid, milk, intracellular fluid, carnivore urine) commonly dependent on biotransformation for termination of activity but may also be excreted unchanged in urine and/or bile some drugs actively secreted into bile... 

To explain the other characteristics of sulfonamide secretion, I considered a unit volume of blood in a gastric mucosa that is secreting at the rate of R ml min . The blood contains the drug at activity fp[P], and the drug diffuses into the gastric juice where its activity is [GJ]. The amount diffusing in any instant is dx/dt and... 

An illustration of the essential steps in inhibition of acid secretion by PPIs with pantoprazole as an example. The drug is administered in a gastroprotected formulation and is absorbed in the duodenum or is administered in a reconstituted IV formulation. The acidic, membrane-enclosed space of the active parietal cell s secretory canaliculus accumulates the PPI approximately 1,000-fold (pH 1.0, pKa of drug approximately 4.0) due to protonation of the pyridine. After intramolecular transfer to the N of the benzimidazole, rearrangement of the molecule occurs to form first the cationic thiophilic sulfenic acid and then the sulfonamide, either of which reacts rapidly with cysteines on the luminal face of the pump. 

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