N5-Formyl-FAH4 (folinic acid; leucovorin)
N10-Formyl-FAH4 Figure 6.10 • (Continued)
Crystalluria and the pKa
Despite the tremendous ability of sulfanilamide to effect cures of pathogenic bacteria, its benefits were often offset by the propensity of the drug to cause severe renal damage by crystallizing in the kidneys. Sulfanilamides and their metabolites (usually acetylated at N4) are excreted almost entirely in the urine. The pKa of the sulfonamido group of sulfanilamide is 10.4, so the pH at which the drug is 50% ionized is 10.4. Obviously, unless the pH is above the pKa, little of the water-soluble salt is present. Because the urine is usually about pH 6 (and potentially lower during bacterial infections), essentially all of the sulfanilamide is in the relatively insoluble, nonionized form in the kidneys. The sulfanilamide coming out of solution in the urine and kidneys causes crystalluria.
Early approaches to adjusting the solubility of sulfanil-amide in the urine were the following:
1. Greatly increasing the urine flow. During the early years of sulfonamide use, patients taking the drugs were cautioned to "force fluids." The idea was that if the glomerular filtration rate could be increased, there would be less opportunity for seed crystals to form in the renal tubules.
2. Increasing the pH of the urine. The closer the pH of the urine is to 10.4 (for sulfanilamide itself), the more of the highly water-soluble salt form will be present. Oral sodium bicarbonate sometimes was, and occasionally still is, given to raise urine pH. The bicarbonate was administered before the initial dose of sulfanilamide and then prior to each successive dose.
3. Preparing derivatives of sulfanilamide that have lower pKa values, closer to the pH of the urine. This approach has been taken with virtually all sulfonamides in clinical use today. Examples of the pKa values of some ionizable sulfonamides are shown in Table 6.8.
4. Mixing different sulfonamides to achieve an appropriate total dose. The solubilities of the sulfonamides are independent of each other, and more of a mixture of sul-fanilamides can stay in water solution at a given pH than can a single sulfonamide. Hence, trisulfapyrimidines, USP (triple sulfa), contain a mixture of sulfadiazine, sul-famerazine, and sulfamethazine. Such mixtures are seldom used today, however, because the individual agents have sufficiently low pKa values to be partially ionized and adequately soluble in the urine, providing that at least the normal urine flow is maintained. Patients must be cautioned to maintain a normal fluid intake; forcing fluids, however, is no longer necessary.
The newer, semisynthetic sulfonamides possess lower pKa values because electron-withdrawing, heterocyclic rings are attached to N1, providing additional stability for the salt form. Hence, the drugs donate a proton more easily, and the pKa values are lowered. Simpler electron withdrawing groups were extensively investigated but were found to be too toxic, poorly active, or both.
Metabolism, Protein Binding, and Distribution
Except for the poorly absorbed sulfonamides used for ulcerative colitis and reduction of bowel flora and the topical burn preparations (e.g., mafenide), sulfonamides and trimethoprim tend to be absorbed quickly and distributed well. As Mandell and Petri noted, sulfonamides can be found in the urine "within 30 minutes after an oral dose."108 The sulfonamides vary widely in plasma protein binding; for example, sulfisoxazole, 76%; sulfamethoxazole, 60%; sulfamethoxypyridazine, 77%; and sulfadiazine, 38%. (Anand102 has published an excellent table comparing the percentage of protein binding, lipid solubility, plasma halflife, and N4 metabolites.) The fraction that is protein bound is not active as an antibacterial, but because the binding is reversible, free, and therefore active, sulfonamide eventually becomes available. Generally, the more lipid soluble a sul-fonamide is, at physiological pH, the more of it will be protein bound. Fujita and Hansch113 have found that among sulfonamides with similar pKa values, the lipophilicity of the
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