Pharmacodynamic Aspects of Tolbutamide, Glibenclamide

Home , Glibornuride, Glisoxepide, Tolbutamide

Diabetologia 7, 449--454 (1971) by Springer-Verlag 1971

Pharmaeodynamic Aspects of Tolbutamide, (llibenclamide, Glibornuride and Glisoxepide I. Dose Response Relations and Repeated Administration in Diabetic Subjects

E. HAUPT, W. K6BERICtt, J. BI~YEIr and K. SC~6~LI~G Department of Endocrinology, Center of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany l%eeeived: June 5, 1971, accepted: October 8, 1971

Summary. Pharmacodynamic studies were performed effets sont contraires aux rdsultats des recherches prdcd- using tolbutamide, glibenclamide, glibornuride (Ro dentes d'autres auteurs. Les concentrations d'insuline 6-4563) and glisoxepide (BS 4231). The four compounds provoqudes par les substrances injectdes sont indiqudes et were administered intravenously, and exact dose-response compardes. relations were established, ealeulating the ED 30 of the decrease in blood glucose in healthy volunteers. Ac- Pharmakodynamik yon Tolbutamid, Glibenclamid, Gli- cordingly, the dose corresponding to the ED 30 was given bornurid und Glisoxepid. I. Dosiswirkungsbeziehungen and twice with a three hour interval to maturity-onset dia- wiederholte Anwendung bei Diabetikern betics. Different dynamics of insulin response were observed Zusammenfassung. Vergleiehende klinisch-experimen- after tolbutamide, glibornuride and glisoxepide on the one belle Untersuchungen wurden mit Tolbutamid, Glibenela- hand, and glibenelamide on the other. In contrast to other mid, Glibornurid (Ro 6-4563) und Glisoxepid (BS 4231) reports in the literature, an obvious uniformly weaker durchgefiihrt. Zun~chst wurden exakte Dosiswirkungsbe- degree of insulin secretion was seen after each of the ziehungen aufgestellt, die dureh i.v. Gabe der vier Sub- different sulphonylurea compounds when given re- stanzen an Stoffwechselgesunden ermittelt wurden. Auf- peatedly. grund dieser Untersuehungen wurde die ED 30, bezogen auf den Blutzuckerabfall, erreehnet. Daraufhin warden Comparaison des actions pharmacodynamiques de nou- die vier Sulfonylharnstoffe in der Dosierung der ED 30 velles substances du type des sulfonylurdes hypoglycgmiantes Altersdiabetikern zweimal im Abstand yon drei Stunden I. Les relations entre les doses des substances et leur effica- intravenSs appliziert. Es zeigte sieh ein deutlicher Unter- citgs. Applications r@dtdes aux sujets diabdtiques sehied in der Dynamik der Insulinsekretion nach Tolbu- Rdsumg. Deux types d'expgrimentations ont 6t6 rd- tamid, Glibornurid und Glisoxepid einerseits und Gliben- alisds: 1. Tolbutamide, glibenclamide, glibornuride (Ro clamid andererseits. Im Gegensatz zu anderen Untersu- 6-4563) et glisoxepide (BS 4231) ont did appliqudes par ehungsgruppen wurde bei allen vier Prgparaten deutlieh voie intraveineuse aux sujets normaux pour ddterminer niedrigere Insulinspiegel nach der zweiten Stimulation les doses exactes, qui diminuent la concentration du glu- festgestellt als naeh der ersten Gabe. cose du sang de 30% (ED 30). 2. Ces doses (ED 30) ont dtd appliqudes aux diabdtiques Agds, deux fois dans un inter- Key words: Tolbutamide, glibenclamide, glibornuride valle de trois heures. La deuxigme injection de routes les (Ro 6-4563), glisoxepide (BS 4231), i.v. dose response re- substances provoquait des concentrations d'insuline in- lations, dynamics of insulin secretion, repeated adminis- fdrieures en eomparaison avec les rdsultats initiaux. Ces tration of sulphonylurea compounds.

A great number of sulphonylurea compounds has glibenclamide [14, 20]. When oral hypoglycaemic been developed since the introduction of carbutamide agents were introduced for therapy of diabetes, one of and tolbutamide for therapy of diabetes mellitus more the most important questions was whether the degree than 15 years ago. In 1966 glibenelamide was discov- of beta-cell stimulation decreased or increased after ered, a substance with an hitherto unknown blood application of these substances. Thus, under certain glucose-lowering potency. The mechanism of action of conditions, maturity-onset diabetics have failed to all these drugs is based on the release of stored pancre- show a satisfactory increase of serum insulin and a atic insulin, though a variety of quantitative [2, 16, subsequent decrease of blood glucose after repeated 21, 22, 23, 24, 25] and qualitative [7, 8, 10, 11, 13, 18] administration of tolbutamide at 24-h intervals [19]. differences has been described for the action of gliben- In contrast, investigations by Raptis et al. [20] indi- clamide. cated that two repeated administrations of glibenela- Recently, some new sulphonylureas with a high mide with a 4-h interval cause an equally high increase potency similar to that of glibenclamide have been in serum insulin and decrease of blood glucose. In presented. The main purpose of this study was to find respect to these contradictory papers in the literature, out exact dose-response relations of these compounds the present report will demonstrate the effects of compared with tolbutamide. Furthermore, certain tolbutamide, glibenclamide and the recently developed differences in the dynamics of insulin secretion were sulphonylurea compounds on the discussed parameters. investigated, as already published for tolbutamide and 450 E. Haupt et al. : Pharmacodynamic Aspects of Tolbutamide I. Diabetologia

Materials and Methods Analytical procedures. Blood glucose was measured Experimental subjects. The subjects studied were by the procedure of tIoffman [12] with a Technieon normal healthy volunteers, and diabetics with a mild autoanalyzer; serum insulin by the immunoassay metabolic disorder and fasting blood glucose levels of of Meade and Klitgaard [15] in the modified form of about 150 rag%. No patient was under any treatment ?r et al. [17]; and free fatty acids by the method at the time of the study except dietetic regulations. of Dole and Meinertz [5]. Decrease of blood glucose, Oral hypoglyeaemic agents had been withdrawn for at as well as the decrease of free fatty acids, were expressed least 48 h. All persons were of normal weight. in per cent of the starting levels. The results were sta- Experimental design. First of all, the dosage tistically evaluated according to Student's t-test. causing a 30% decrease of blood glucose from the baseline level (ED 30), as described by Freriehs and Results Puls [6], was determined after intravenous application Determination of the ED 30: The effect of tolbut- of tolbutamide, glibenelamide, glibornuride (Ro 6-4563) amide, glibenclamide, glibornuride and glisoxepide on and glisoxepide (BS 4231)} The four substances were blood glucose is shown in Fig. 1. Minimum blood given to the same five healthy volunteers in three glucose levels were usually obtained after dO rain. different amounts. Samples for determination of blood However, the maximal effect of glibenclamide was glucose, free fatty acids and serum insulin were found somewhat later when small dosages were given. obtained at 0, 5, 10, 20, 40, 60 and 90 min. The ED 30 Using higher doses of this compound, maximal activi- of each compound was evaluated. Having established ties for lowering blood glucose were observed earlier.

Blood glucose Blood glucose decrease [% l decreose[~/o ]

0 X Tol butami de Glli4b;n41E~ rn i de 0 10 10 "\\\ 5,5mg tkg 20 20

30 3O ~/10,0 mg/kg ZO 40

50 5O

0- Glibor nuride ~xx Glisoxepide 0 {Ro 6-L563) 10 10 /kg --4 ,~

20 20 ~.... 0,12mg lkg ~/~~ 30 30 mg/kg 40 40

50 50

5' 10' 20' 40' 60' 90" 5" 10' 20' 40' 60' 90' mln. Fig. 1. Changes in blood glucose in 5 healthy volunteers following i.v. application of different sulphonylureas in various doses. (Mean of starting levels • SEN : 95.8 ~: 1.07 rag%) these data, t0 non-obese, maturity-onset diabetics Fig. 2 demonstrates the insulin response to the received the four substances over several days. The four compounds. Two different types of the dynamics ED 30 was administered twice with a 3-h interval. of insulin secretion were observed: tolbntamide, Samples were obtained at 0, 5, 10, 20, 40, 60, 90, 120, glibornuride and glisoxepide caused an immediate 180, 185, 190, 200, 240 and 270 min. All tests were sharp peak of serum insulin with effective levels carried out starting at 8 a.m. under resting conditions continuing for about 20 min; when glibenclamide was after an overnight fast. given, however, there was both a delayed output of serum insulin and a plateau-like maximum with effective concentrations lasting for about 60 rain. I We are indebted to the I-Ioffmann La-l%oehe Inc. for the gift of glibornuride (1%o 6-4563) and ~o the Bayer Equipotent doses of these compounds causing a 30% and Schering Incs. for the gift of glisoxepide (BS 4231). decrease of blood glucose were 7.5 mg tolbutamide, Vol. 7, No. 6, 1971 E. :Kaupt et al. : Pharmacodyllamlc Aspects of Tolbutamide I. 45i

IRI IRI uUIml uU/ml

Tolbutomide Glibenclam de T I HB 4~g) t100 !00 i i

10,0 mg/kg ,J ,[ O.01mglkg I ~. 50 50

5,5rag/k! 0

Glibornuride GlisoxeDde !00 /~,[ IRe 6-45631 ( BS L231 ', 100

' k'~X 0'03 mg/kg I

so 1~ 50

5' 10' ~' &O' 60' 90' 5' 10' 20" 40' ~' 9dmin

Fig. 2. Variations in immunoreactive insulin (IRI) in 5 healthy voluteers following i.v. application of various sulphonylureas in different (loses

Decreose of Deacrease of blood glucose hood glucose 1%] 1 ...... ][%] i

0 *

10 -<._ !0

20 ""-. r~ i, I 20

30 o oTo,,butomide i '\ 30 ...... olibenclQmide i \-:~ ~2 *--~ C,]isoxepide ~ Glibornuri de

5 20' 40' 60' 90' 120' 180' 200' 220' 240' 270' rain t~'ig. 3. Variations in blood glucose in 10 maturity-onset diabetics following i.v. administration of two repeated doses of the various sulphonylureas with a 3-hour interval, the doses being the ED 30 evaluated in healthy normals. (Mean of starting levels :~ St!]SI: 158 ~ 4.3 mg%) 452 E. Haupt et al. : Pharmacodynamie Aspects of Tolbutamide I. Diabetologia

Decreose of DecreGse of FFA[%] FFA [%]

c ~ ToIbutomide .... ~ Gtibenclamide +10 ~ Olisoxepide .10 -a Glibornuride

-10 -10 i

-20

30 - 30 I

5' 20' 40" 60' 90' 120' 18C 200 22U 240' 270' rain, Fig. 4. Variation in free fatty acids (FFA) in 10 maturityonset diabetics following i.v. administration of two repeated doses of the various sulphonylureas with a 3-h interval, f,he doses being the ED 30 evMua~ed in healthy normMs. (~Iean of starting levels i SE3/I: 887 ~ 26.6 FE/1)

!RI IR! ~uU/ ml pU ]ml

70 t 70

~ I I i l

"--~.

-I 2 "7 c o Tolbutqmide 30 f x ...... x Glibenclomide q" 30 o--,--~ Olisoxepide a z Gtibornuride

5' 10' 20' 40' 50' 90' 150" 180' 190' 200' 220 ' 240' 270'min. Fig'. 5. Variations in immunoreactive insulin (I1%I) in 10 maturity-onset diabetics following i.v. administration of two repeated doses of various sulphonylureas with ~ 3-h intervM, the doses being the ED 30 of blood gIucose decrease evaluated in heaIthy normMs Vol. 7, No. 6, 1971 E. Haupt et al. : Pharmacodynamic Aspects of Tolbutamide I. 453

0.006 mg glibenclamide, 0.12 mg glibornuride and 0.02 to oral administration. Previous reports [9] and mg glisoxepide per kg body weight. studies performed by Bigler et al. [3] and by Christ et Response to repeated administration: As Fig. 3 al. [4] indicated that tolbutamide, glibornuride and indicates, the four compounds caused an almost linear glisoxepide have an absorption rate of about 90%, and decrease in the levels of blood glucose. The effect of ghbenelamide of only less than 50%. In spite of the the four drugs in lowering blood glucose was almost different degrees of absorption, examinations con- the same, and with no statistical difference using the cerning the oral ED 30 of tolbutamide and glibencla- ED 30. As a matter of fact, the dosages chosen for this mide performed by Frerichs and Puls [6], indicated a part of the experiment seemed to be comparable for surprising conformity with the amounts of the ED 30 diabetic subjects also. obtained by our intravenous experiments (i. e. 5.74 mg Similar observations were obtained for the levels of tolbutamide and 0.0084 mg glibenclamide per kg body- free fatty acids (FFA) (Fig. 4). An immediate initial weight). Tolbutamide and glibenclamide were orally ad- rise, probably due to a short-lasting release of ministered as solutions or suspensions of the pure sub- catecholamines, is followed by a distinct decrease of stances by these authors, whereas the other studies on FFA-levels to about 25%. Maximal antilipolytic the degree of absorption were performed with tablets of activities were found after 90 min. The second in- quantitatively and qualitatively the same composition jection caused a further decrease lasting for one hour as for the normal tablet preparation. Thus, it appears only. Depressions of FFA-levels after tolbutamide, that suspensions of the two sulphonyhrea derivatives ghbornuride and ghsoxepide were absolutely similar, are absorbed more quickly and obviously to a much whereas the decrease after glibenclamide continued for higher degree compared with the administration of 4.5 h. Measurement of glycerol levels showed almost tablets, thus giving serum concentrations approxi- similar results. mately similar to those obtained by intravenous in- Dynamics of insulin release again indicated the jections. Distinct differences were observed in the characteristic differences between tolbutamide, gli- dynamics of insulin secretion. Glibornuride and bornuride and gtisoxepide on the one hand and ghben- ghsoxepide caused a sharp initial increase of serum clamide on the other (Fig. 5). The first three substances insulin levels lasting for a relatively short time. In caused maximal serum insulin levels already 5 min contrast to this tolbutamide-type of stimulation, after injection. After 10 min, the concentrations had glibenclamide showed its well-known delayed insulin dropped more than 50%. A repeated injection after response with a plateau-like maximum [10, 13, 20]. the 3-h interval caused only a slight increase in serum After administration of tolbutamide, glibornuride or insulin. Such peaks were significantly lower than those glisoxepide, healthy subjects showed, surprisingly, a observed after the first stimulation. In accordance much smaller decrease in blood glucose than did with the blood-glucose-lowering activity and the diabetics, despite a higher total output of insulin. The decrease of free fatty acids, the profiles of insulin maximal decrease in blood glucose was obtained in secretion after tolbutamide, glibornuride and ghsox- healthy subjects at 40 rain, whereas this was pro. epide did not show significant differences. In contrast, longed in diabetics for 3 h. These findings may be serum insulin levels after glibenelamide were signif- explained by even a slight hypoglycaemia in healthy icantly higher 60 and 90 min after injection (p ~ 0.05) subjects causing glycogenolysis in the liver. when compared with those after the three other drugs. The findings obtained with glibenclamide are quite Apart from the observed differences, glibenclamide different. In diabetics, administration of ghbenclamide and the other compounds were similar in respect of gave an output of insulin that was considerably higher reduced insulin peaks after repeated administration. than that given by the other compounds, but with no difference in the lowering of the blood glucose. Data presented by B~nder et al. [1] indicated a certain effect Discussion of sulphonylurea compounds on the adrenal medulla. It seems possible that glibenelamide, more than other Our results demonstrate the strong beta-cytotropic sulphonylurea derivatives, stimulates the adrenal activity of all the sulphonylurea compounds investi- medulla, thus mobilizing liver glycogen by mean of gated in this study. As this is already known for gliben- release of catecholamines. This would result in a clamide, the new drugs acted in the range of a few balance between increased levels of blood glucose on milligrams. However, comparing the ED 30 after i.v. the one hand and increased levels of serum insulin on administration, glibenclamide was found to be 1250 the other. The extent of antilipolysis would be con- times more potent than tolbutamide, whereas glibor- sistent with this inference. nuride and glisoxepide revealed only a 63 and 375 times It is quite surprising that in previous studies an higher potency respectively. Since differences in blood- equally high output of insulin was reported after two glucose-lowering activities were similar when given to repeated i.v. administrations of glibenclamide [20]. normal subjects and diabetics, these relations may be This effect was seen in both healthy subjects and vahd for both groups. Since there are differences in the maturity-onset diabetics. The present study does not degree of absorption, these data cannot be transfered confirm these results. Distinctly lower increases in

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