Effects of Glipizide on the Pharmacokinetics of Carvedilol after Oral and Intravenous Administration in Rats

( Chong Ki Lee ),( Jun Shik Choi ) 한국응용약물학회 2011 Biomolecules & Therapeutics(구 응용약물학회지) Vol.19 No.2

This study was designed to investigate the effects of glipizide on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Clinically carvedilol and glipizide can be prescribed for treatment of cardiovascular diseases as the complications of diabetes, and then, Carvedilol and glipizide are all substrates of CYP2C9 enzymes. Carvedilol was administered orally or intravenously without or with oral administration of glipizide to rats. The effects of glipizide on cytochrome P450 (CYP) 2C9 activity and P-gp activity were also evaluated. Glipizide inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 18 μM. Compared with the control group, the area under the plasma concentration-time curve (AUC) was significantly increased by 33.0%, and the peak concentration (Cmax) was significantly increased by 50.0% in the presence of glipizide after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.13- to 1.33-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of glipizide was increased by 36.8%. After intravenous administration, compared to the control, glipizide could not significantly change the pharmacokinetic parameters of carvedilol. Therefore, the enhanced oral bioavailability of carvedilol may mainly result from inhibition of CYP2C9- mediated metabolism rather than both P-gp-mediated efflux in the intestinal or in the liver and renal elimination of carvedilol by glipizide.

다시마 식이가 흰쥐에서 글리피지드의 체내동태에 미치는 영향

최한곤,장보현,이종달,유봉규,용철순 한국약제학회 2003 Journal of Pharmaceutical Investigation Vol.33 No.2

Drug interactions with food, on occasion, lead to serious nutritional and functional changes in the body as well as alternations of pharmacological effect. It, therefore, should be necessary to take drug interactions with food into consideration for effective and safe therapeutics. Diabetes mellitus is a heterogeneous group of disorders characterized by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with increase risk of micovascular, macrovascurlar, and neuropathic complications. However, the precise mechanixm of diabetes mellitus remains unclear. Three basic objectives in the care of diabetic patients are maintaining optimal nutrition, avoiding hypo- or hyperglycemia and preventing complications. The purpose of this study was to investigate the effect of Laminaria japonica diet on the absorption, distribution, metabolism and excretion of glipizide which are frequently used in the treatment of diabetes. Diabetic rats induced by streptozotocin were employed in this study. Blood concentrations of oral hypoglycemic agents were measured by HPLC and resultant pharmacokinetic parameters were calculated by RSTRIP. The mechanisms of drug interaction with food were evaluated on the basis of pharmacokinetic parameters such as k_a, t_1/2, C_max, t_max, and AUC. Administration of glipzide in normal rats treated with Laminaria japonica diet showed significant increase in AUC, k_a, t_1/2, t_max and decrease in C_max, compared to those without Laminaria japonica diet. This might result from adsorption of glipizide on components of Laminaria japonica, causing delayed absorption. Administration of glipizide in diabetic rats treated with Laminaria japonica diet showed significant increase in t_1/2 and t_max, and decrease in C_max, compared to those without Laminaria japonica diet. This might also result from adsorption of glipizide on components of Laminaria japonica, causing delayed absorption and flattened blood concentration of glipizide. The oral glucose test showed that Laminaria japonica diet could lower blood glucose level probably through either inhibiting the activity of disaccharidases, intestinal digestive enzymes, or delaying the absorption of glucose. More studies should be followed to fully understand pharmacokinetic changes of glipizide caused by long-term Laminaria japonica diet.

Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects

Nam-Tae Kim,Chang-Keun Cho,Pureum Kang,Hye-Jung Park,Yun Jeong Lee,Jung-Woo Bae,Choon-Gon Jang,Seok-Yong Lee 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.2

Glipizide is a second-generation sulfonylureaantidiabetic drug. It is principally metabolized to inactivemetabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the eff ects of CYP2C9*3 and*13 variant alleles on the pharmacokinetics and pharmacodynamicsof glipizide. Twenty-four healthy Korean volunteers(11 subjects with CYP2C9*1/*1 , 8 subjects withCYP2C9*1/*3 , and 5 subjects with CYP2C9*1/*13 ) wererecruited for this study. They were administered a singleoral dose of glipizide 5 mg. The plasma concentration ofglipizide was quantifi ed for pharmacokinetic analysis andplasma glucose and insulin concentrations were measured aspharmacodynamic parameters. The results represented thatCYP2C9*3 and *13 alleles signifi cantly aff ected the pharmacokineticsof glipizide. In subjects with CYP2C9*1/*3and CYP2C9*1/*13 genotypes, the mean AUC 0–∞ wereincreased by 44.8% and 58.2%, respectively (both P < 0.001),compared to those of subjects with CYP2C9*1/*1 genotype,while eff ects of glipizide on plasma glucose and insulinlevels were not signifi cantly diff erent between CYP2C9genotype groups. In conclusion, individuals carrying the defective CYP2C9*3 and CYP2C9*13 alleles have markedlyelevated plasma concentrations of glipizide comparedwith CYP2C9*1/*1 wild-type.

Rat에서 Cromakalim에 의해 유발된 혈관이완 및 혈압강하작용에 대한 Glipizide의 억제작용

허인회(In Hoi Huh),안형수(Hyung Soo Ann),윤성훈(Seong Hun Yoon) 大韓藥學會 1991 약학회지 Vol.35 No.3

The inhibitory effects of glipizide on cromakalim-induced relaxation of aortae and hypotension in the anesthetized rats was examined. In rat thoracic aortic rings pre-contracted with norepinephrine, cromakalim produced a relaxation sustainedly. This relaxation was completely inhibited by pre- or post-treatment of glipizide. In the anesthetized rat, cromakalim produced a rapid and sustained fall in the arterial blood pressure. This hypotensive action of cromakalim was abolished by pre- or post-treatment of glipizide. It is suggested that glipizide is the potent inhibitor of cromakalim, K+ channel opener, in the rats.

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).

흰쥐의 척수에서 Cyclic Nucleotides 및 Glipizide가 Baclofen의 심혈관반응에 미치는 영향

고현철,하지희,신인철,Koh, Hyun-Chul,Ha, Ji-Hee,Shin, In-Chul 대한약리학회 1997 The Korean Journal of Physiology & Pharmacology Vol.1 No.6

The purpose of present study is to investigate the influence of a spinal gamma-aminobutyric acid B($GABA_B$) receptor on a central regulation of blood pressure(BP) and heart rate(HR), and to define its mechanism in the spinal cord. In urethane-anesthetized, d-tubocurarine-paralyzed and artificially ventilated male Sprague-Dawley rats, intrathecal administration of drugs were carried out using injection cannula(33-gauge stainless steel) through the guide cannula(PE 10) which was inserted intrathecally at lower thoracic level through the puncture of a atlantooccipital membrane. Intrathecal injection of an $GABA_B$ receptor agonist, baclofen(30, 60, 100 nmol) decreased both BP and HR dose-dependently. Pretreatment with 8-bromo-cAMP(50 nmol), a cAMP analog, or glipizide(50 nmol), a ATP-sensitive $K^+$ channel blocker, attenuated the depressor and bradycardic effects of baclofen(100 nmol), but not with 8-bromo-cGMP(50 nmol), a cGMP analog. These results suggest that the $GABA_B$ receptor in the spinal cord plays an inhibitory role in central cardiovascular regulation and that this depressor and bradycardic actions are mediated by the decrease of cAMP via the inhibition of adenylate cyclase and the opening of $K^+$ channel.

흰쥐에서 글리피지드가 로살탄의 약물동태에 미치는 영향

유진욱(Jin Wook Yoo),최진석(Jin Seok Choi),최준식(Jun Shik Choi) 大韓藥學會 2011 약학회지 Vol.55 No.3

The present study was to investigate the effect of glipizide on the pharmacokinetics of losartan in rats. Losartan was administered intravenously (3 mg/kg) and orally (9 mg/kg) in the presence and absence of glipizide (0.3 and 1 mg/kg) to rats. The pharmacokinetic parameters of losartan were significantly altered by the presence of glipizide compared with the control group (given losartan alone). Presence of glipizide significantly (p

글리피짓 체내동태 연구를 위한 혈청 중 글리피짓의 HPLC 정량법 검증

조혜영 ( Hea Young Cho ),이화정 ( Hwa Jeong Lee ),최후균 ( Hoo Kyun Choi ),이용복 ( Yong Bok Lee ) 전남대학교 약품개발연구소 2005 약품개발연구지 Vol.14 No.-

Determination of Glimepiride in Human Plasma by Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry

Kim, Ho-Hyun,Chang, Kyu-Young,Lee, Hee-Joo,Han, Sang-Beom Korean Chemical Society 2004 Bulletin of the Korean Chemical Society Vol.25 No.1

A sensitive method for quantitation of glimepiride in human plasma has been established using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS). Glipizide was used as an internal standard. Glimepiride and internal standard in plasma sample was extracted using diethyl etherethyl acetate (1 : 1). A centrifuged upper layer was then evaporated and reconstituted with the mobile phase of acetonitrile-5 mM ammonium acetate (60:40, pH 3.0). The reconstituted samples were injected into a $C_{18}$ reversed-phase column. Using MS/MS in the multiple reaction monitoring (MRM) mode, glimepiride and glipizide were detected without severe interference from human plasma matrix. Glimepiride produced a protonated precursor ion ([M+H]$^+$) at m/z 491 and a corresponding product ion at m/z 352. And the internal standard produced a protonated precursor ion ([M+H]]$^+$) at m/z 446 and a corresponding product ion at m/z 321. Detection of glimepiride in human plasma by the LC-ESI/MS/MS method was accurate and precise with a quantitation limit of 0.1 ng/mL. The validation, reproducibility, stability, and recovery of the method were evaluated. The method has been successfully applied to pharmacokinetic studies of glimepiride in human plasma.

인체간 microsome에서의 제 2세대 sulfonylurea계 약물들의 cytochrome P450 약물 대사효소에 대한 억제작용

최지이,김수영,김경아,박지영 침례병원 2003 浸禮病院學術誌 Vol.19 No.-