Comparison of the pharmacokinetics and pharmacodynamics of two commercial products containing glibenclamide

N A L

A R T I C L E

Comparison of Pharmacokinetics and Pharmacodynamics of Shortand Long-Term Glyburide Therapy in NIDDM

G

lyburide, a second generation sulfonylurea agent, is increasingly being prescribed for the treatment of patients with type II diabetes. Glyburide exerts its hypoglycemic actions by stimulating the release of pancreatic insulin, suppressing hepatic glucose output, and augmenting peripheral glucose uptake (1-3). Several studies have examined the pharmacological and pharmacokinetic characteristics of the agent (1-7). The majority of previous studies were of short LINDA A. JABER, PHARMD RICHARD L. SLAUGHTER, MS duration and were performed in healthy EDWARD J. ANTAL, PHD IAN R. WELSHMAN, MS subjects. The results of these studies may not be directly applicable to patients with OBJECTIVE — To examine the pharmacokinetics and pharmacodynamics of gly- diabetes who require chronic glyburide buride after single- and multiple-dose administration in patients with type II diabetes. dosing. Glyburide exhibits a complicated RESEARCH DESIGN A N D METHODS— Twenty patients with type II diapharmacokinetic profile that appears to betes between 40 and 70 years of age participated in the study. A 24-h pharmacokinetic be a function of the specific formulation evaluation including a 4-h Sustacal tolerance test was conducted before instituting glyburide therapy (baseline), after the first 2.5-mg test dose of glyburide and at weeks used, the study population, and duration 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated with a target goal of therapy. The precise description of the of achieving a fasting plasma glucose of ^7.8 mmol/1 or to reach maximum daily doses pharmacokinetics of glyburide with time has been hindered by the sensitivity limof 20 mg. itations of the specific analytical method RESULTS — A significant prolongation in the elimination half-life (t1/2: week 0,4.0 used. In general, data from studies using a ± 1.9 h; week 6, 13.7 ± 10.5 h; and week 12, 12.1 ± 8.2 h) and an increased volume specific and sensitive high-performance of distribution of glyburide was observed during chronic dosing. These results strongly liquid chromatography (HPLC) method suggest possible drug accumulation. No differences in pharmacokinetic parameters indicated that glyburide pharmacokinetwere noted between evaluations at week 6 or week 12. Changes in pharmacodynamic ics were best described by a two-compartresponse of glucose, insulin, and C-peptide to chronic glyburide therapy were obment open model (4). served. Glyburide therapy significantly reduced plasma glucose levels at weeks 6 and The duration of the elimination 12 (percent changes in AUC0_>4 g i ucose from baseline: week 0, — 3 ± 11%; week 6 , - 2 9 half-life of the drug has been extensively ± 13%; and week 12, —26 ± 19%). Pancreatic insulin secretion was acutely enhanced debated. It appears to be strongly depenand maintained during long-term therapy. Responsiveness to therapy as assessed by dent on the specific formulation and the the ratio of AUC0_>4 glucose:AUC0_>4 c . peptide was significantly improved at all weeks route of administration (4). The mean compared with baseline. No pharmacodynamic response differences were observed elimination half-life for the oral glyburide between the week 6 and the week 12 evaluations. tablet preparation is reported to range CONCLUSIONS— This study demonstrates that significant differences in gly- from 4 to 11 h (4). However, the prolonburide pharmacokinetics and pharmacodynamics exist between single-dose and gation of the terminal elimination half-life steady-state conditions. These differences support the need for careful dosage titration and possible accumulation of the drug of glyburide to achieve a desired therapeutic response in patients with type II diabetes. with repeated dosing was observed by Balant et al. (7). Although a dose-response relationship or an association beFrom the Department of Pharmacy Practice, Wayne State University, Detroit, and the Clinical tween half-life and duration of action has Pharmacokinetics Unit, The Upjohn Company, Kalamazoo, Michigan. not been consistently established, a reAddress correspondence and reprint requests to Linda A. Jaber, PharmD, Department of cent study conducted in healthy volunPharmacy Practice, Wayne State University, 328 Shapero Hall, Detroit, MI 48201. teers demonstrated that glyburide is effecReceived for publication 18 January 1994 and accepted in revised form 30 June 1994. HPLC, high-performance liquid chromatography; BMI, body mass index; FPG, fasting plasma tive within a narrow therapeutic range glucose; Cl, clearance; HDL, high-density lipoprotein; AUC, area under the curve. (8). These characteristics of glyburide may be of clinical significance.

1300

DIABETES CARE, VOLUME 17, NUMBER 11, NOVEMBER

1994

Jaber and Associates

• WEEK o • WEEK 6 A WEEK 12

glyburide dosage titration period. The usual dietary and exercise habits of each patient were continued during the study, and specific therapeutic instructions on diet or exercise were not provided. Subjects were informed of the objectives, design, and possible risks of the study before signing a written informed consent to enroll in the study. The protocol was approved by the human and animal investigation committee of Wayne State University.

Design Initially, patients discontinued their current hypoglycemic therapies during a 2-week washout period. At the end of this period, and after an overnight fast, subjects consumed Sustacal liquid (238 ml; 0 .5 1 1.5 2 3 4 6 8 10 12 24 33.6 gcarbohydrate, 14.7 g protein, 5.6 g Time (Hours) fat) for a baseline glucose tolerance evalFigure 1—Mean glyburide serum concentrations (±SD) after thefirstdose at week 0 and weeks 6 and uation before initiating glyburide therapy 12 oj chronic therapy. (week — 1). Blood samples for glucose, insulin, and C-peptide determinations were This study was designed to examTwenty patients (11 women and 9 collected at time 0 (just before Sustacal ine the pharmacokinetics and pharmaco- men) completed the entire study. Their ingestion), and at 0.5, 1,2, and 4 h after dynamics of glyburide after single- and mean age (±SD) was 57.5 ± 12.4 years, ingestion. Patients were then started on multiple-dose administration and to de- mean total body weight was 89.4 ± 22.4 12-week chronic glyburide therapy with scribe the clinical significance of the phar- kg, mean percent above ideal body weight an initial dosage titration period. Addimacokinetic changes that occur during was 42.5 ± 31.8%, and mean body mass tionally, a 24-h pharmacokinetic evaluachronic therapy. A portion of the data col- index (BMI) was 31.5 ± 9.2 kg/m2. The tion, including a 4-h Sustacal tolerance lected in this study has previously been patients had diabetes for a mean of 6.1 ± test, was conducted after the first 2.5-mg analyzed and demonstrated the lack of in- 5.3 years, and the baseline mean serum test dose of glyburide (week 0) and at fluence of obesity on the pharmacokinet- creatinine (±SD) was 88 ± 22 jamol/l. weeks 6 and 12 of chronic glyburide therics and pharmacodynamics of glyburide Before enrollment, 19 patients had been apy. After an overnight fast, patients were after 12 weeks of therapy (9). treated with sulfonylureas for a mean of admitted to the diabetes care unit. An 183.2 ± 3.2 years, and 1 was ineffectively gauge angiocatheter was inserted into a treated by diet alone. Eleven patients forearm vein for blood sampling. An oral RESEARCH DESIGN AND METHODS — Patients with type II di- were currently being treated for hyper- glyburide solution (2.5 ml, 1 mg/ml) was abetes who were between 40 and 70 years tension. Of these,fivepatients were main- administered and was immediately folof age were screened before participation tained on diuretics, six on calcium chan- lowed by 238 ml of Sustacal liquid that in the study. A comprehensive physical nel antagonists, five on angiotensin- was ingested within a 10-min period. examination, a complete medical history, converting enzyme inhibitors, and two on Blood samples were collected immediand a baseline laboratory evaluation were clonidine (the majority were on multiple ately before the glyburide dose and at 0.5, obtained at screening. Subjects with a his- drug regimens). Four patients had been 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after the tory of insulin therapy and associated ke- taking nonsteroidal anti-inflammatory dose. Standardized meals were provided toacidosis, clinical or biochemical evi- agents for osteoarthritis. Nondiabetic 4 and 8 h after the dose. All serum samdence of renal or hepatic disorders, medications were kept unchanged during ples obtained were analyzed for glyunstable myocardial disease, or a docu- the study with the exception of two pa- buride, while samples collected at 0, 0.5, mented allergy to sulfa drugs were ex- tients whose antihypertensive medication 1, 2, 4, 6, 12, and 24 h were analyzed for regimen had to be adjusted during the glucose, insulin, and C-peptide concencluded. CD

DIABETES CARE, VOLUME 17, NUMBER 11, NOVEMBER

1994

1301

Glyburide therapy in NIDDM

Table \—Glybviride pharmacokinetic parameters at weeks 0, 6, and 12

Time of peak Week 0 6 12

1.9 ± 1.5 1.1 ±0.9 1.7 ± 1.3

Maximum concentration Cmax (ng/ml)

Rate of elimination Kjh" 1 )

Half-life t1/2 (h)

Clearance

177 ± 75 268 ± 240* 278 ± 146*

0.209 ± 0.095 0.077 ± 0.047* 0.08 ± 0.047*

4.0 ± 1.9 13.7 ± 10.5* 12.1 ±8.2*

3.8 ± 1.3 2.6 ± 1.3* 3.2 ± 2.1

Free clearance Clf(l/h) 4,190 ± 1,560 2,767 ± 1,481* 3,298 ± 2,006*

Volume of distribution

v d (D 20 ± 9 41 ±27 51 ± 51*

Data are means ± SD. * Statistically different from week 0 values, P ^ 0.05.

trations. The same procedure was followed for all three admissions. Individual glyburide dosage regimens were titrated to achieve targeted fasting plasma glucose concentrations (FPG) of ^7.8 mmol/1 or until a maximum daily dose of 20 mg was reached. Starting at 2.5-5 mg, daily glyburide doses were adjusted by 2.5-5 mg weekly according to plasma glucose responses. Daily doses of 4 gi U C O S (/AUC 0 _ > 4 c-peptide

Insulin Fasting Insulin (pmol/1)

AUC o _ >4 (pmol-r 1 -h" 1 ) Change in A U C 0 ^ (%) C-peptide Fasting C-peptide (nmol/1)

AUCo^^mol-r^h"1) Change in AUQ,^ (%)

Baseline

WeekO

Week 6

Week 12

60.6 ± 13.0

58.2 ± 13.5 - 3 ± 11 4.1 ± 1.9*

43.0 ± 10.7*T - 2 9 ± 13t 3.2 ± 1.4*t

43.6 ± 10.9*t - 2 6 ± 19t 3.2 ± 1.4*t

88.2 ± 76.3 864 ± 462* 85 ± 73

90.3 ± 65.4 696 ± 426 39 ± 32t

101 ± 77.8 810 ± 504* 73 ± 6 9

0.78 ± 0.26 5.30 ± 1.66* 38 ± 2 9

0.89 ± 0.38*t 4.97 ± 1.66* 34 ± 34

0.83 ± 0.28 4.97 ± 1.32* 33 ± 2 9

—

5.8 ±2.5 79.8 ± 66.3 534 ± 414 —

0.75 ± 0.28 3.91 ± 1.49 —

Data are means ± SD. * Significantly different from baseline (week — 1), P £ 0.05. t Significantly different from week 0, P ^ 0.05.

1302

DIABETES CARE, VOLUME 17,

NUMBER 1 1 , NOVEMBER

1994

Jaber and Associates

25n

O • • •

WEEK -1 WEEK 0 WEEK 6 WEEK 12

20-

15-

10-

C9

5-

0 .5

1

2

4 Time (Hours)

6

12

24

Figure 2—Mean glucose serum concentrations (±SD) after a Sustacal challenge test at baseline before glyburide therapy (week —1), and weeks 0, 6, and 12 ofglyburide therapy.

curves for free glyburide concentrations (AUC0_>24 giy f) were calculated by multiplying AUC0_>24 giy by the free fraction. Apparent oral clearance (Cl) was calculated as the administered dose (2.5 mg) divided by the area under serum concentration curve (AUQ^oo)- Because the test dose differed from the daily steady-state dose, AUC0_>oo was calculated as

peptide (AUCo^c.peptide) after the Sustacal challenge were estimated by the linear trapezoidal rule. These parameters were normalized for differences in glyburide concentrations by dividing the corresponding AUC by AUCo^^^y and AUC 0 _» 4gly f. The percent change in AUCs from baseline Sustacal meal challenge tests for glucose, insulin, and Cpeptide were also computed.

AUC0_>a, = AL7C0_>24 "*" Q A ~ ^ e where AUC0_>24 is the area under the serum concentration versus time profile from 0 to 24 h after test-dose administration, and Co and C24 are the glyburide serum concentrations at the 0 and 24 h times during the test-dose intervals, respectively. Clearance of free glyburide (Clf) was calculated as the clearance divided by the free fraction. The apparent volume of distribution (Vd) was calculated as clearance divided by Ke. For pharmacodynamic analyses, the areas under the serum concentrations curves from 0 to 4 h for glucose (A\JC0_^ glucose), insulin ( A U C o ^ j ^ J , and C-

DIABETES CARE, VOLUME 17,

NUMBER 1 1 ,

Statistical analysis Statistical analysis testing differences between single and chronic dosing were performed using the two-tailed Student's t test. Bonferroni's (Dunn) t test was used to determine differences between weeks for all subjects. All data are expressed as means ± SD. P < 0.05 was considered statistically significant. RESULTS Pharmacokinetics The glyburide serum concentration-time profiles measured at week 0 and after 6

NOVEMBER

1994

and 12 weeks of chronic therapy are shown in Fig. 1. The pharmacokinetic parameters measured after the administration of the 2.5 mg of glyburide oral solution during these three evaluation intervals are represented in Table 1. Mean tmax values did not significantly change from baseline after chronic therapy. Mean Cmax values were significantly increased from the first dose at both weeks 6 and 12 as a result of the increased daily glyburide dosages at steady state (week 6, 12.9 ± 7.5 mg; week 12, 14.8 ± 7.5 mg). Significant changes in Kel and tl/? were observed between the first dose (week 0) and chronic dosing (weeks 6 and 12). Mean t1/2 was increased at weeks 6 and 12, respectively. The increase in the elimination half-life was observed in every subject, except for two in whom tU2 was slightly reduced with chronic dosing. Likewise, the volume of distribution was increased. No association between body weight or BMI and these pharmacokinetic characteristics was observed. None of these pharmacokinetic parameters changed significantly between the 6- and 12-week evaluations. Clearance, however, showed a significant reduction at week 6 compared with weeks 0 and 12, while clearance of free glyburide was significantly reduced at both weeks 6 and 12 compared with week 0 values. Pharmacodynamics The pharmacodynamic data for glucose, insulin, and C-peptide responses to the Sustacal meal challenge at baseline (week — 1), and at week 0, week 6, and week 12 are depicted in Table 2. Figures 2,3, and 4 are graphic representations of serum glucose, insulin, and C-peptide concentrations, respectively. The AUC0. ^ R1UCOSC values were significantly reduced (P — 0.0001) at weeks 6 and 12 compared with baseline or week 0 values. The percent decrease in AUC0_>4 glueosc from baseline in response to glyburide therapy was significantly greater at weeks 6 and 12 compared with week 0 (P = 0.0001). Similar glucose response to glyburide was noted when these areas were corrected by the

1303

Glyburide therapy in NIDDM

600-

500-

O WEEK -1 • WEEK 0 • WEEK 6 • WEEK 12

portional decrease in A U C Q ^ glucose relative to the observed increase in AUC0^4.c-peptide o v e r time > resulting in an overall decrease in the ratio and indicating an increased responsiveness.

Glycemic control and daily dosages The mean FPG concentrations were significantly lowered at week 4 (9.5 ± 2.6 mmol/1), and were sustained through 2 300week 12 of glyburide therapy (9.6 ± 2.2 mmol/1) compared with baseline (15.0 ± 3.2 mmol/1). The hypoglycemic effects of 200glyburide were more pronounced on the fasting compared with the nonfasting hyperglycemia. The FPG fell by ~36% from 100 baseline to week 12, and there was ~ 2 1 % reduction in the postprandial Cmax levels over the same time period (baseline, 17.5 i r 24 ± 3.1; week 0, 18.3 ± 3.4; week 6, 13.5 12 0 .5 1 ± 2.8; and week 12,13.9 ± 2.9 mmol/1). Time (Hours) A significant decline in fructosamine conFigure 3—Mean insulin serum concentrations (±SD) after a Sustacal challenge test at baseline before centrations versus baseline (3.7 ± 0.6 glyburide therapy (week —1), and weeks 0, 6, and 12 of glyburide therapy. mmol/1) was observed at week 4 (3.3 ± 0.6 mmol/1) and continued unchanged to week 12 (3.2 ± 0.5 mmol/1). HbAlc contotal and free glyburide AUC. No phar- icantly increased from baseline after the first centrations were similarly reduced at macodynamic differences in glucose re- glyburide dose and at weeks 6 and 12. The week 8 (10.7 ± 2.2%) and week 12 (10.5 sponse were observed between week 6 percent change in AUC0^4_c.peptide from ±2.3%) compared with baseline (12.6 ± baseline was not different between the 2.0%). The mean final daily dose of glyand 12 evaluations. Baseline insulin and C-peptide three evaluations after initiation of gly- buride was 14.8 ± 7.5 mg. Thirteen paconcentrations during the Sustacal chal- buride therapy. The peak C-peptide con- tients were maintained on the maximum lenge were significantly changed in re- centrations (week — 1, 1.15 ± 0.39 daily dose of glyburide (20 mg). To predict if there is a relationship sponse to glyburide treatment. A signifi- nmol/1; week 0,1.56 ± 0.47 nmol/1; week 6,1.52 ± 0.55 nmol/1; and week 12,1.48 between severity of the diabetic condition cant increase in insulin was seen ± 0.51 nmol/1) were significantly inand the response to glyburide, compariafter the first glyburide dose (week 0) and at the final week 12 evaluation but creased (P = 0.0001) compared with sons were made between subjects who not at week 6. The percent increase in baseline, although tmax values did not dif- were divided into groups according to A U Q . ^ insuiin from baseline was also sig- fer. All of these parameters were compa- baseline FPG levels. Group A (n = 9) innificantly lower at week 6 compared with rable at weeks 0, 6, and 12. Fasting C- cluded those subjects who had a baseline week 0 and 12. Peak insulin concentra- peptide levels differed significantly from FPG 13.9 mmol/1. FPG and than baseline at all evaluation points, alThe responsiveness of the patients daily doses of glyburide differed signifithough the time to reach peak concentra- was assessed by comparing the ratio of the cantly between groups at every evaluation tions (t max ) values were not different the week throughout the study. In addition, •.glucose u ^0—»4.C-peptide (Cmax: baseline, 204 ± 138; week 0, 354 test meal at baseline and weeks 0, 6, and fewer patients in group A required the ± 192; week 6,288 ± 198; week 12,342 12. These values decreased significantly maximum daily dose (22%) compared ± 246 pmol/1; P = 0.0009). Mean fasting at all weeks compared with baseline (Ta- with subjects in group B (91%) by the end insulin concentrations were not different ble 2). Values at weeks 6 and 12 were not of the study. However, the percent from baseline during glyburide therapy. significantly different but were signifi- change in FPG from baseline was not difThe C-peptide areas under the se- cantly decreased from week 0. These ferent between the two groups at week 4 rum concentration time curves were signif- changes were caused by a larger than pro- ( - 3 5 ± 8% for group A vs. - 3 7 ± 12% 400-

1304

DIABETES CARE, VOLUME 17, NUMBER 11, NOVEMBER 1994

Jaber and Associates

2.5-i

O • • •

WEEK-1 WEEK 0 WEEK 6 WEEK 12

~ 2.0"5 E B

I 1.5H

Ia> u c

5

1.0H

B.

o

.5-

12

0 .5 1

24

of this phenomenon, the investigators postulated the presence of a third slowly equilibrating compartment that becomes apparent with multiple dosing. However, Balant's findings have been questioned. His observations were attributed to a lack of specificity of the radioimmunoassay used, which is known to measure the parent drug and its metabolites, and attributed to the delayed or prolonged absorption of the early European glyburide formulation used in the study (4). Rogers et al. (11), using HPLC, found no evidence of a third compartment when glyburide was given intravenously to healthy subjects. However, Rogers et al. could not exclude the presence of such a compartment because serum glyburide concentrations were below the limits of the assay sensitivity.

Time (Hours)

Our study confirms Balant's original observations of glyburide accumulaFigure 4—Mean C-peptide serum concentrations (±SD) after a Sustacal challenge test at baseline tion in patients receiving chronic therapy. before glyburide therapy (week —1), and weeks 0, 6, and 12 ofglyburide therapy. These pharmacokinetic changes over time would appear to reflect primarily for group B) and remained unchanged chronic glyburide therapy in patients distributional changes as indicated by the throughout the remainder of the study with type II diabetes have not been clearly change in the calculated volume of distri(week 12: —34 ± 10% for group A and described in previous investigations. This bution. However, changes in elimination - 4 4 ± 10% for group B). study extends our knowledge of the phar- did contribute, as indicated by a reducmacokinetic profile of glyburide after sin- tion in both clearance and free clearance. gle- and multiple-dosing conditions, as It is important to note, however, that the Serum lipids A significant reduction in the mean week well as the acute and chronic effects of the observed delay in elimination with long12 total cholesterol concentration com- drug on plasma glucose, insulin, and C- term therapy was not associated with exaggerated clinical response since it did pared with baseline was observed (4.78 ± peptide concentrations. not contribute to an increase in the num1.16 vs. 5.35 ± 1.29 mmol/1; P = Of particular importance in our ber of hypoglycemic events. 0.0001). Although the mean final serum pharmacokinetic analysis was the obserconcentrations of triglycerides, low-den- vation of an approximately threefold inChronic glyburide administration sity lipoprotein, very-low-density li- crease in the elimination half-life of gly- reduced plasma glucose levels effectively, poprotein, and HDL were lower than at buride after 6 and 12 weeks of therapy. although complete normalization of glybaseline, these changes did not reach sta- The pharmacokinetic characteristics of cemic control was not achieved in ~50% tistical significance. the terminal elimination phase of the of the study participants. Failure to drug have been controversial. The obser- achieve euglycemia can be linked to the vation of delayed hypoglycemia many lack of dietary control during the study. Adverse reactions Three patients experienced symptomatic hours after administration of glyburide Maximal reduction in hyperglycemia was hypoglycemic episodes that were mild in led Balant et al. (6,7) to investigate possi- seen after 4 weeks of glyburide therapy nature. These events were documented ble accumulation of the drug upon re- and was maintained relatively unchanged by home capillary glucose measurements peated dosing. In a study of six patients for the remaining 8 weeks. Glyburide and were properly managed by the pa- with diabetes given 5 mg of glyburide provoked a greater therapeutic effect on daily for 15 days, there was an upward fasting than postprandial hyperglycemia. tients. trend in mean serum concentrations and FPG levels were reduced by ~36%, CONCLUSIONS— The pharmaco- a significant prolongation of the apparent whereas the maximum plasma glucose kinetics and pharmacodynamics of plasma half-life of the drug (7). As a result levels attained in response to the glucose

DIABETES CARE, VOLUME 17,

NUMBER 11, NOVEMBER

1994

1305

Glyburide therapy in NIDDM

challenge decreased by ~ 2 1 % . This is consistent with previous observations of potent glyburide-induced suppression of basal hepatic glucose production, a main determinant of FPG levels (3,12,13). In addition, the effectiveness of glyburide to achieve euglycemia seems to be dependent on the initial degree of hyperglycemia. Patients initially presenting with FPG concentrations of 13.9 mmol/1. Glyburide therapy acutely enhanced insulin secretion. After the first dose, the mean increase in the maximum postprandial insulin levels was ~66%, while the mean maximum postprandial C-peptide concentrations increased by 36%. This difference in glyburide effect on insulin and C-peptide concentrations has been reported previously and is perhaps related to a reduction in hepatic insulin extraction during sulfonylurea therapy (3). These increases in insulin and Cpeptide levels continued throughout the study. Only minimal increases were observed in fasting insulin and C-peptide concentrations during glyburide administration. The insulinotropic effect of chronic sulfonylurea therapy has been extensively debated. Previous studies have shown that plasma insulin levels increase with initiation of sulfonylurea therapy and then return to pretreatment levels during long-term therapy (1,14,15). Our data suggest a persistent elevation of postprandial (but not fasting) insulin levels during chronic sulfonylurea exposure. These results could reflect a direct effect of the stimulating action of glyburide on the pancreatic /3-cells after a meal and the inhibitory effect of the attenuated hyperglycemia on insulin release during the fasting state. In summary, the observed pharmacokinetic profile of glyburide differs between acute and chronic administra-

1306

tion. The pharmacokinetic changes indicate the possibility of glyburide accumulation during chronic dosing with no apparent increase in the incidence of adverse events. The insulinotropic effect of glyburide is maintained during long-term therapy, which would exclude the possibility of glyburide-induced exhaustion or desensitization of /3-cells. These findings support the necessity for the initiation of glyburide therapy at the lowest possible doses, followed by careful dose titration to achieve the desired therapeutic response in patients with type II diabetes.

6.

7.

8.

9. Acknowledgments— This study was supported by a grant from The Upjohn Company in Kalamazoo, Michigan. This study originated at Wayne State University, Department of Pharmacy Practice, Detroit, Michi10. gan. These data were presented in part at the 19th Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, Nevada, November 1990. This study was previously published in abstract form in J Clin Pharmacol 11. 30:842, 1990.

References 1. Kolterman OG: Longitudinal evaluation of the effects of sulfonylurea therapy in subjects with type II diabetes mellitus. Am ] Med 79 (Suppl. 3B):23-33, 1985 2. Gavin JR: Dual actions of sulfonylureas and glyburide: receptor and post-receptor effects. Am] Med 79 (Suppl. 3B):34-42, 1985 3. Groop L, Groop PH, Stenman S, Saloranta C, Totterman KJ, Fyhrquist F, Melander A: Comparison of pharmacokinetics, metabolic effects and mechanisms of action of glyburide and glipizide during long-term treatment. Diabetes Care 10: 671-678, 1987 4. Pearson JG: Pharmacokinetics of glyburide. Am] Med 79 (Suppl. 3B):67-71, 1985 5. Rogers HJ, Spector RG, Morrison PJ, Bradbrook ID: Pharmacokinetics of intravenous

12.

13.

14.

15.

glibenclamide investigated by a high performance liquid chromatographic assay. DiabetologLa 23:37-40,1982 Balant L, Zahnd GR: Comparison of the pharmacokinetics of glipizide and glibenclamide in man. Eur J Clin Pharmacol 8:63-69, 1975 Balant L, Zahnd GR, Weber F, Fabre J: Behavior of glibenclamide on repeated administration to diabetic patients. Eur ] ClinPharmacol 11:19-25, 1977 Groop LC, Barzilai N, Ratheiser K, Luzi L, Wahlin-Boll E, Melander A, DeFronzo RA: Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans. Diabetes Care 14:724-727,1991 Jaber LA, Antal EJ, Slaughter RL, Welshman IR: The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics. Eur] Clin Pharmacol 45:459-463, 1993 Addison TE, Knuth DW, Hopkins NK, Brisson J: Determination of glyburide in human serum and plasma by HPLC with deuterium source fluorescence detection. Pharm Res 7 (Suppl.):S8, 1990 Rogers HJ, Spector RG, Morrison PJ, Bradbrook ID: Pharmacokinetics of intravenous glibenclamide investigated by a high performance liquid chromatographic assay. Diabetologia 23:37^0, 1982 Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, DeFronzo RA: Mechanisms of improvement in glucose metabolism after chronic glyburide therapy. Diabetes 33:838-845, 1984 Groop L, Wahlin-Boll E, Groop P-H, Totterman KJ, Melander A, Tolppanen E-M, Fyhrquist F: Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetes. Eur] Clin Pharmacol 28:697-704, 1985 Elkeles RS, Heding LG, Paisey RB: The long-term effect of chlorpropamide on insulin, C-peptide and proinsulin secretion. Diabetes Care 5:427-429, 1982 Duckworth WC, Solomon SS, Kitabchi AE: Effect of chronic sulfonylurea therapy on plasma insulin and proinsulin levels. J Clin Endocrinol Metab 35:585-591, 1972

DIABETES CARE, VOLUME 17,

NUMBER 1 1 ,

NOVEMBER

1994