Sulfonylurea metabolism

Romesser JA, DP O Keefe (1986) Induction of cytochrome P-450-dependent sulfonylurea metabolism in Streptomyces griseolus. Biochem Biophys Res Comm 140 650-659. 

Sulfonylurea herbicides are generally applied to crops as an early post-emergent herbicide. Crops that are tolerant to these herbicides quickly metabolize them to innocuous compounds. At maturity, residues of the parent compound in food and feed commodities are nondetectable. Metabolites are not considered to be of concern, and their levels are usually nondetectable also. For this reason, the residue definition only includes the parent compound. Tolerances [or maximum residue limits (MRLs)] are based on the LOQ of the method submitted for enforcement purposes and usually range from 0.01 to 0.05 mg kg (ppm) for food items and up to O.lmgkg" for feed items. There is no practical need for residue methods for animal tissues or animal-derived products such as milk, meat, and eggs. Sulfonylurea herbicides are not found in animal feed items, as mentioned above. Furthermore, sulfonylurea herbicides intentionally dosed to rats and goats are mostly excreted in the urine and feces, and the traces that are absorbed are rapidly metabolized to nontoxic compounds. For this reason, no descriptions of methods for animal-derived matrices are given here. 

Metformin also has been shown to produce beneficial effects on serum lipid levels and thus has become a first-line agent for type 2 DM patients with metabolic syndrome. Triglyceride and low-density lipoprotein (LDL) cholesterol levels often are reduced by 8% to 15%, whereas high-density lipoprotein (HDL) cholesterol improves by approximately 2%. A modest weight loss of 2 to 3 kg (4.4—6.6 lb) also has been reported with metformin therapy. Metformin often is used in combination with a sulfonylurea or a thiazolidinedione for synergistic effects. 

Y = yes, N = no) Sulfonylureas Brand (mg) Nonetderty Elderly Dose (mg) (mg/day) Action Metabolism or Therapeutic Notes... 

Sulfonamides Sulfonylureas, phenytoin, warfarin Decreased metabolism of other agent Monitor blood glucose, SDC, PT... 

Diabetic patients Weight-loss induction by orlistat may be accompanied by improved metabolic control in diabetic patients, which might require a reduction in dose of oral hypoglycemic medication (eg, sulfonylureas, metformin) or insulin. Misuse potential As with any weight-loss agent, the potential exists for misuse of orlistat in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia). 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

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. 

Mechanism of Action Afirst-generation sulfonylurea that promotes release of insulin from beta cells of pancreas. Therapeutic Effect Lowers blood glucose concentration. Pharmacokinetics Rapidly absorbed from the gastrointestinal (Gl) tract. Protein binding 60%-90%. Extensively metabolized in liver. Excreted primarily in urine. Removed by hemodialysis. Half-life 30-42 hr. 

Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short, with an elimination half-life of 4-5 hours, and it is best administered in divided doses. Because of its short half-life, it is the safest sulfonylurea for elderly diabetics. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some sulfonamides) that inhibit the metabolism of tolbutamide. 

Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action. Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours. Its half-life is about 7 hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required, the dose should be divided and given twice daily. 

Increased hepatic metabolism of tolbutamide and probably other sulfonylureas metabolized by the liver (including chlorpropamide). 

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