Pharmacokinetic and Pharmacodynamic Characterization of Gliclazide in Healthy Volunteers

Kim, Ho-Soon,Yun, Min-Hyuk,Kwon, Kwang-Il The Pharmaceutical Society of Korea 2003 Archives of Pharmacal Research Vol.26 No.7

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers; Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration ($\Delta$PG), by area under the increase of glucose concentration-time curve ($AUC_{$\Delta$PG}$) or by the difference in increase of glucose concentration ($D_{$\Delta$PG}$) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that $C_{max}, T_{max}$, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were $4.69\pm1.38 mg/L, 3.45\pm1.11 h, 1.26\pm0.35 L/h, 17.78\pm5.27 L, and 9.99\pm2.15 h$, respectively. When compared with the no drug administration group, gliclazide decreased significantly the $AUC_{$\Delta$PG}$ s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The $\Delta$PGs were positively correlated with $AUC_{gliclazide}$ at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The $AUC_{$\Delta$PG}$s were positively correlated with $AUC_{gliclazide}$ at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The $D_{$\Delta$PG}$ reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.

Pharmacokinetic Drug Interaction between Nifedipine and Gliclazide

임태환,김양우,최인 한국병원약사회 2016 病院藥師會誌 Vol.33 No.1

Gliclazide and nifedipine have been clinically prescribed for the prevention or treatment of cardiovascular diseases with diabetes. However, these drugs have potential interaction. The purpose of this study was to investigate the possible effects of gliclazide on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. We evaluated the effect of gliclazide on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine after oral and intravenous administration of nifedipine to rats in the presence or absence of gliclazide (1.0 and 4.0 mg/kg). Gliclazide inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibitory concentration (IC50) of 12.5 μM. The areas under the plasma concentration-time curve (AUC0-∞) and the peak concentration (Cmax) of nifedipine were significantly (4.0 mg/kg, P<0.05) increased by 39.0% and 34.8%, respectively, in the presence of gliclazide, as compare to those of control. In addition, the total body clearance (CL/F) was significantly (4.0 mg/kg, P<0.05) decreased by the treatment with gliclazide (47.9%). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of gliclazide (4.0 mg/kg) was significantly (P<0.05) higher (39.2%) than that of the control group. The metabolite-parent AUC ratio (MR) of nifedipine was significantly decreased by treatment with gliclazide (19.8%). The AUC0-∞ of intravenous nifedipine was significantly (4.0 mg/kg, P<0.05) higher than that of the control group (18.1%), which suggested that gliclazide inhibited the metabolism of nifedipine. The increased bioavailability of nifedipine in the presence of gliclazide may be due to an inhibition of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and gliclazide-mediated reduction of CL/F of nifedipine.

2형 당뇨병에서 Repaglinide의 유용성에 대한 연구

박철영,김영설,이현철,장학철 대한당뇨병학회 2001 임상당뇨병 Vol.2 No.4

연구배경 : 제2형 당뇨병 환자의 치료에 새로운 약제인 repaglinide와 기존에 상용하던 gliclazide를 비교하여 repaglinide의 유효성 및 안정성을 비교 평가 하고자 하였다. 방법 : 154명의 환자를 1:1 비율로 repaglinide와 gliclazide군으로 무작위 배정하였다. 약제 투여 전에 탈락된 2명을 제외한 152명의 환자 중 127명의 환자가 투약을 마쳤다. 투약 방법은 2주간의 약제 중지 기간 후에 4주동안 약제 용량 결정 기간을 통해 결정된 용량을 8주간 지속적으로 투여 하였다. 약제 용량은 repaglinide는 0.5mg, 1mg 또는 2mg 1정을 매 주식사 전에 경구 투여하였으며, gliclazide는 80mg 1정 또는 1/2정으로 시작해 제품 설명서에 따라 투여하였다. 치료 전 후의 당화혈색소, 공복혈당, 식후혈당 및 지질대사 지표 등의 검사로 유효성을, 여러 가지 생화학적,혈액학적 검사 및 저혈당빈도 등으로 안정성을 각각 평가하였다. 결과 : 12주 투여 후 repaglinide군과 gliclazide군 모두에서 당화혈색소 및 공복혈당의 유의한 감소를 보였다. 그러나 당화혈색소 및 공복혈당의 감소 정도는 두 군간의 유의한 차이는 없었다. 60분 및 90분의 식후혈당의 변화값의 평균은 repaglinide군에서는 기저치와 비교하여 유의하게 감소하였지만, gliclazide군에서는 유의한 감소를 보이지 않았다. 그러나 두 군의 60분, 90분 및 120분에서의 식후혈당 감소 정도는 두 치료군간에 유의한 차이는 없었다. 총콜레스테롤의 값의 유의한 감소가 gliclazide군에서 있었지만 변화 정도는 두 치료군간의 차이가 없었다. 체중변화는 두 군간 통계학적으로 유의한 차이가 없었다. 두 군모두 우려할 만한 약제 이상반응은 없었다. 저혈당 증상은 gliclazide군이 repaglinide군보다 많았지만 두 군간에 유의한 차이는 없었다. 결론 : 제2형 당뇨병 환자에서 repaglinide는 혈당조절에 대하여 gliclazide와 동등한 유효성을 가지고 있으며 안전한 것으로 사료된다. Background : This study was designed to compare the efficacy and safety of repag linide with gliclazide in a 12-week open-labelled, randomized, parallel group, multi-center study of outpatients with type 2 diabetes. Methods : A total of 182 patients were screened . 154 patients were randomized in a 1:1 ratio of repaglinide (78 patients) and gliclazide (76 patients). Two randomized patients withdrew from the trial prior to receive any trial medication. At the end of trial, 127 patients completed. The study protocol included a screening visit to assess patient eligibility; a washout period of 2 weeks, a titration period of 4 weeks, and a subsequent 8 week maintenance period. Repaglinide was a dministered preprandially with the three main meals, and gliclazide was taken according to the product labeling . Results : After 12 weeks treatment, both repaglinide and gliclazide resulted in significant reductions in HbA_(1c) (p<0.001; both treatment groups) and fasting blood glucose (FBG) values (p<0 .001; both treatment groups). Significant reductions in postprandial blood glucose (PPBG) values were found in the repaglinide group at 60 minutes (p<0.05) and at 90 minutes (p<0.05). However, no significant treatment differences in HbA 1c, FBG, or PPBG were observed. Both number of patients and frequency of reported hypoglycemic events appeared to be lower in the repaglinide group than in the gliclazide group (not significant). Conclusion: Overall, the results showed that repaglinide is well-to lerated and equally effective in controlling HbA_(1c), FBG and PPBG as gliclazide.

Pharmacokinetic and Pharmacodynamic Characterization of Gliclazide in Healthy Voiunteers

HosoonKim,MinhyukYun,Kwang-ilKwon 대한약학회 2003 Archives of Pharmacal Research Vol.26 No.7

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers; Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration (DPG), by area under the increase of glucose concentration-time curve (AUCDPG) or by the difference in increase of glucose concentration (DDPG) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that Cmax, Tmax, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were 4.69±1.38 mg/L, 3.45±1.11 h, 1.26±0.35 L/h, 17.78±5.27 L, and 9.99±2.15 h, respectively. When compared with the no drug administration group, gliclazide decreased significantly the AUCDPG s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The DPGs were positively correlated with AUCgliclazide at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The AUCDPGs were positively correlated with AUCgliclazide at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The DDPG reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.

Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects

Pureum Kang,Chang-Keun Cho,Choon-Gon Jang,Seok-Yong Lee,Yun Jeong Lee,Chang-Ik Choi,Jung-Woo Bae 대한약학회 2023 Archives of Pharmacal Research Vol.46 No.5

Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined CYP2C9 and CYP2C19. The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC0–∞ (P < 0.001), and 57.1 and 32.3% lower CL/F (P < 0.001), compared to those of the no defective allele group (group 1), respectively. The CYP2C9IM–CYP2C19IM group had AUC0–∞ increase of 1.49-fold (P < 0.05) and CL/F decrease by 29.9% (P < 0.01), compared with the CYP2C9 Normal Metabolizer (CYP2C9NM)–CYP2C19IM group. The CYP2C9NM–CYP2C19PM group and CYP2C9NM–CYP2C19IM group showed 2.41- and 1.51-fold higher AUC0–∞ (P < 0.001), and 59.6 and 35.4% lower CL/F (P < 0.001), compared to those of the CYP2C9NM–CYP2C19NM group, respectively. The results represented that CYP2C9 and CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of CYP2C19 had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of CYP2C9 also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the CYP2C9–CYP2C19 genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.

Gliclazide, a K_ATP channel blocker, inhibits vascular smooth muscle cell proliferation through the CaMKKβ–AMPK pathway

Lee, Kyung Young,Kim, Jae-Ryong,Choi, Hyoung Chul Elsevier 2018 Vascular pharmacology Vol.102 No.-

<P><B>Abstract</B></P> <P>Gliclazide, a sulfonylurea that is widely used to treat type II-diabetes, specifically blocks K<SUB>ATP</SUB> channels and recombinant smooth muscle (SUR2B/Kir6.1) K<SUB>ATP</SUB> channels with high potency. Furthermore, it exerts antioxidant properties and inhibits tumor cell proliferation. In this study, we investigated the inhibitory effect of gliclazide on vascular smooth muscle cell (VSMC) proliferation and tried to identify the underlying signaling pathway. We first investigated the effect of gliclazide-induced AMP-activated protein kinase (AMPK) activation on the proliferation of VSMCs. Gliclazide induced phosphorylation of AMPK in a dose- and time-dependent manner and inhibited VSMC proliferation following stimulation by platelet-derived growth factor (PDGF). However, K<SUB>ATP</SUB> channel openers and Kir6.1 siRNA prevented gliclazide-mediated inhibition of VSMC proliferation. Gliclazide also increased the levels of Ca<SUP>2+</SUP>/calmodulin-dependent protein kinase kinase β (CaMKKβ), an upstream kinase of AMPK. These findings suggested that the effects of K<SUB>ATP</SUB> channels on AMPK activity were mediated by the regulation of intracellular Ca<SUP>2+</SUP> levels. Oral administration of 2mg/kg gliclazide resulted in the activation of CaMKKβ and AMPK in vivo, suggesting that gliclazide suppressed VSMC proliferation via the CaMKKβ–AMPK signaling pathway. Taken together, our observations indicated that gliclazide-induced AMPK activation may act to prevent diabetes-associated atherosclerosis.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

경구용 혈당강하제인 gliclazide의 식전30분과 식후30분 복용에 따른 혈당치의 비교

이은경,박의순,김수영,황인홍 한국병원약사회 1997 병원약사회지 Vol.14 No.4

This study was designed to compare the blood glucose levels when gliclazide was administered to the DM patients 30 minutes before and after meal. We selected 14 patients according to specific guidelines. Patients were divided into two groups. One group was administered gliclazide 30 minutes before meal and the other group was administered gliclazide 30 minutes after meal. After one month, both groups had standard meals (75 g OGTT), and then, blood glucose was measured every 30 minutes for two hours. After the first month, the groups switched administering times. After one month, blood glucose was measured as before. AUC was obtained from the curve of blood glucose concentration for the two groups, but differences between the groups were not significant (p>0.05). This result have shown that the administration time of gliclazide in relation to the meal should lay emphasis on compliance with patients.

Therapeutic Effects of Coptidis Rhizoma and Berberine in Streptozotocin-induced Diabetic Rats

Kee-Tae Kweon,Sang-young Ahn,In-hye Ham,Kyung-jin Lee,Ho-Young Choi 대한한의학회 2011 대한한의학회지 Vol.32 No.6

Therapeutic Effects of Coptidis Rhizoma and Berberine in Streptozotocin-induced Diabetic Rats

Kweon, Kee-Tae,Ahn, Sang-Young,Ham, In-Hye,Lee, Kyung-Jin,Choi, Ho-Young The Society of Korean Medicine 2011 대한한의학회지 Vol.32 No.6

Objectives: We performed this study to compare the antidiabetic effects of Coptidis Rhizoma (CR) and its major component berberine with gliclazide. Materials and Methods: Diabetic rats induced by injection of streptozotocin (STZ) 55mg/kg were treated with CR 100, 200, 400mg/kg and berberine 100mg/kg. After rats were treated for 5 days, serum glucose, total cholesterol, triglyceride, BUN, creatinine and antioxidant levels were determined. Results: The cytotoxic effects of CR (0.1, 0.01, and 0.001mg/mL), berberine and gliclazide ($0.1{\mu}M$, $1{\mu}M$, and $10{\mu}M$) were tested in rat insulinoma (RIN) cells induced with 5mM STZ. The levels of fasting blood glucose, total cholesterol, triglyceride, BUN and creatinine of CR and berberine treated groups were reduced as much as that of gliclazide group in comparison to control groups, whereas total antioxidant levels increased. In vitro experiments showed that CR and berberine have a cytoprotective effect on RIN cells.

인체 간 Microsome에서의 제2세대 Sulfonylurea계 약물들의 Cytochrome P450 약물 대사효소에 대한 억제작용

최지이,김수영,김경아,박지영 대한내분비학회 2002 Endocrinology and metabolism Vol.17 No.4

연구배경: Sulfonylurea계 약물들은 제2형 당뇨병 치료에 널리 사용되는 약물이다. 장기간 투여로 인한 병용투여 약물과의 약물상호작용 가능성이 높고 또한 이들 약물들과 병용투여 약물간의 상호작용으로 인한 독작용이 보고된 예가 있으나 작용기전을 밝힌 연구는 거의 이루어지지 않고 있는 실정이다. 본 연구에서는 약물대사 효소로서 중요한 역할을 하고 있는 cytochrome P450(CYP)에 대해서 제2세대 sulfonylurea계 약물들에 의하여 억제 작용의 가능성이 있는지를 확인하고 이를 통해 약물상호작용의 가능성을 검증하고자 하였다. 방법: 인체간 microxomes를 이용한 glibenclamide, glipizide, 및 gliclazide 등이 CYP1A2, CYP2C9, CYP2C19, CYP2D6 및 CYP3A4 동효소에 대한 억제정도를 각각의 CYP 동효소에 대한 지표약물을 이용하여 농도에 따른 상대적 억제정도로 평가하였다. 결과: Glibenclamide의 경우 CYP2C9에 대한 강한 억제 작용을 보였으며(IC_50, 11.3μM), CYP3A4에 대해서도 중등도의 억제작용이 관찰되었다(IC_50, 5900μM). 또한, CYP1A2, CYP2C19, CYP2D6에 대해서도 억제 작용이 관찰되었으나 상대적으로 미약하였다(IC_50s>112μM). Glipizide는 CYP3A4에 대해서 선택적으로 강한 억제작용을 보였으며(IC_50, 11.2μM) 타 CYP 동 효소에 대해서는 거의 억제 작용을 나타내지 못하였다(IC_50s>500μM). Gliclazide의 경우 CYP2C9에 대해서는 약한 억제작용이 관찰되었으며(IC_50, 276.1μM) 타 CYP 동효소에 대한 억제 작용은 관찰되지 아니하였다(IC_50, >500μM). 결론: CYP 동효소에 대해서 제2세대 sulfonylurea계 약물들이 억제 작용을 나타낼 수 있음을 확인하였으며 이러한 결과는 임상적으로 sulfonylurea와 병용 투여 약물간의 약물 상호작용의 가능성을 제시하고 있다. 그러므로, Sulfonylurea계 약물과 타 약물의 병용 투여시 치료 영역이 좁은 약물이나 농도에 따른 독성이 큰 약물의 경우 적극적인 혈당 조절과 더불어 병용 투여 약물에 대한 적극적인 감시(monitoring)가 필요할 것으로 사료된다. Background: Sulfonylurea drugs have been used for many decades as one of the main families of drugs for the treatment of type 2 diabetes mellitus. Even though there are many opportunities to medicate sulfonylurea drugs concomitantly with many other drugs, and furthermore there have been several case reports on drug interaction with sulfonylurea drugs, there has been no clear demonstration revealing the mechanisms that cause these interactions. We therefore evaluated inhibitory potential of sulfonylurea drugs, including glibenclamide, glipizide and gliclazide, on the cytochrome P450(CYP)-catalyzing enzymes using human liver microsomes. Methods: The inhibitory effects of glibenclamide, glipizide and gliclazide, on the CYP-catalyzing reaction, were evaluated for CYP1A2, CYP2C19, CYP2D6 and CYP3A4 using human liver microsomes, and probe drugs for each. Results: Glibenclamide showed relative potent inhibitory effects on the CYP2C9- and CYP3A4- catallyzed reaction (IC_50; 11.3(μM and 59.0 (μM). The other CYP isoforms tested showed only weak inhibitory effects by due to glibenclamide (IC_50>112(μM). Glipizide showed potent inhibitory effect on CYP3A4-catalyzed reaction only (IC_50; 11.2 (μM), and weak, or no, inhibitory effects on each on the other CYP isoforms tested (IC_50>276 (μM). Conclusion: The sulfonylurea drugs showed inhibitory potential on the CYP-catalyzing reaction in human liver microsomes. The results obtained in the present study provide insights into the potential of the drug interaction to ward drugs co-administered with sulfonylureas. It will be necessary to take into consideration the control of blood glucose, as well as therapeutic drug monitoring, to reduced toxicities when sulfonylurea drugs are co-administered with drugs of a narrow therapeutic range, or with severe dose-dependent toxicities (J Kor Soc Endocrinol 17:544∼553, 2002).