Tolbutamide
Tolbutamide. First-generation sulfonylurea hypoglycemic for type 2 diabetes. Closes pancreatic β-cell K_ATP channels (SUR1/Kir6.2) →… Oral half-life 6.3 h.
First-generation sulfonylurea hypoglycemic for type 2 diabetes. Closes pancreatic β-cell K_ATP channels (SUR1/Kir6.2) → depolarization → voltage-gated Ca²⁺ entry → insulin secretion. Almost entirely metabolized by CYP2C9 to hydroxymethyl- and carboxytolbutamide — making tolbutamide the canonical CYP2C9 probe substrate in classical DDI studies. Now rarely used clinically (displaced by 2nd/3rd-gen sulfonylureas + GLP-1 agonists + SGLT2 inhibitors) but retained in the registry as the workhorse CYP2C9 probe. PK (Orinase label, 500 mg PO single): Cmax 39-52 mg/L, Tmax 3-4 h, t½ 4.5-6.5 h, F well-absorbed (~80% est), protein binding ~95% (small Vd ~14 L follows). Food does not alter absorption. CYP2C9 substrate — canonical probe for CYP2C9 phenotyping + DDI assessment (fluconazole / sulfaphenazole / aprepitant DDIs documented).
PK: the stored 5.5 h was the MIDPOINT of the approval document range "4.5 to 6.5 hours" and sat below every published human measurement. Replaced by Adebayo 1988 (PMID:3169118), 8 healthy men, verbatim "Control half-life of tolbutamide 6.29 h". V 10.5 L is Williams 1977 (PMID:837649), the only TRUE (intravenous) human volume, verbatim "0.15 +/- 0.03 L/kg" x 70 kg; the stored 14 L was above every measured value. ka 0.5 /h and F 0.8 dropped: neither appears in the approval document, whose only absorption statement is a Tmax of 3 to 4 hours, nor anywhere in PubMed. An apparent volume of 9.1 L exists (PMID:10190649) but must not be paired with a separate bioavailability.
Pharmacokinetics
- Oral — t½ 6.3 h · Vd 10.5 L
Sources: PMID:9068933, PMID:3169118, PMID:837649, PMID:10190649