Glyburide (also known as, e.g., glibenclamide) is a sulfonylurea drug used in treating diabetes. The systematic name of glyburide is 5-chloro-N-(4[N-(cyclohexylcarbamoyl) sulfamoyl]phenethyl)-2-methoxybenzamide. Glyburide preferentially binds to and affects the sulfonylurea receptor 1 (SUR1) but at higher concentrations also binds to and affects the sulfonylurea receptor 2 (SUR2).
Glyburide has been suggested as a therapy for acute stroke (ischemic and hemorrhagic), traumatic brain injury (TBI), spinal cord injury (SCI), myocardial infarction (MI), shock (including hemorrhagic shock), organ ischemia, and ventricular arrhythmias. The pharmacokinetic parameters of intravenous glyburide have been described in numerous publications (see Table 1). All patents and publications discussed herein are hereby incorporated by reference in their entireties.
TABLE 1Pharmacokinetic Parameters of Glyburide after Intravenous AdministrationPublicationMcEwen1Spraul2Rydberg3Rogers4Sorgel5Morrison6Neugebauer7Jonsson8†Patient PopulationNIDDM(NoninsulindependentHealthyHealthyHealthyHealthydiabetesHealthyHealthymales andmales andmales andHealthymales andmellitus) malesmales andmalesfemalesfemalesfemalesmalesfemalesand femalesfemalesN2052 882482010Dose (mg)1.48‡4.0 1.011.52.41.252.0Cmax (ng/mL)———331 ± 65648376196Clearance:2.92‡— 5.46*‡——4.424.411.68‡(L/h)(mL/min)49—91*‡—74.7 ± 22 73.7‡73.5‡101.3Vd (L)9.7‡—10.9*‡—11.22 ± 3  7.411.6‡—Beta (1/h)0.3— 0.52*‡0.517—0.620.38—t1/2 (h)2.461.50 ± 0.361.47 ± 0.421.474.22 ± 1  1.18‡1.821.15Tmax (h)————0.09———Mean subject74.1—74.657-88—69.7——weight (kg)*normalized to 70 kg†Data from Caucasian patients‡Not presented in the publication, data generated from information presented in the publication.AUC, area under the time-concentration curve;Cmax, the maximum concentration of the drug;Vd, the volume of distribution of drug1McEwen, et al. 1982;2Spraul et al. 1989;3Rydberg et al. 1995;4Rogers et al. 1982;5Sorgel et al. 1997;6Morrison et al. 1982;7Neugebauer et al. 1985;8Jonsson et al. 2000.
While the intravenous (“i.v.” or “IV”) glyburide dose in these and other studies was delivered within a few minutes in the majority of studies, several of the studies included continuous infusions of an hour or more. Garrel et al. (1987) administered a 1 mg i.v. bolus dose, followed by 0.3 mg/h for 17 hours, to six subjects with IDDM (insulin-dependent diabetes mellitus); the total dose was 6.1 mg glyburide. In addition, Groop et al. (1987) dosed 16 normal subjects with a total of 2.1 mg over 4 hours, and Neugebauer et al. (1985) dosed ten normal subjects with a total of 2 mg i.v. glyburide over 1 hour.
Doses for bolus infusions (i.e., infusions of three minutes or less) ranged between 1 and 2.4 mg (Rydberg et al. 1994).
The doses and duration of dosing of the studies described above are presented in Table 2.
TABLE 2Dose and Duration of Dosing in Select Clinical Studies of Intravenous Glyburide.Garrel GroopNeugebauerRydberg Banket al. et al. et al. et al. et al. 19871987198519942000N61610812Bolus dose1 mg0.84 mgN/A2.4 mg—Duration 17 hours4 hours1 hour—10 minof infusionInfusion0.3 mg/hr0.35mg/hr2 mg/hr—6 mg/hrdose/hrBolus dose1 mg0.84mgN/A2.4 mg—Total dose6.1 mg2.1mg2 mg2.4 mg1 mg
Maximum glyburide plasma concentrations were provided for some studies, and ranged from 200-436 ng/mL (Rogers et al. 1982; Groop et al. 1987; Bank et al. 2000; Jonsson et al. 2000). Subjects in the study by Groop et al. (1987), who received a bolus dose followed by continuous i.v. infusion, reached a mean glyburide Cmax of 240 ng/mL after administration of the bolus, and a steady-state concentration of 88-93 ng/mL during the 220 minutes of continuous infusion.
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