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| Pharmacokinetics and Metabolism: Glipizide is rapidly and completely absorbed following oral administration in an immediate release dosage form. The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes. Beginning 2 to 3 hours after administration of GLUCOTROL XL Extended Release Tablets, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of GLUCOTROL XL Extended Release Tablets, effective plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide. The mean relative bioavailability of glipizide in 21 males with type 2 diabetes after administration of 20 mg GLUCOTROL XL Extended Release Tablets, compared to immediate release Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with GLUCOTROL XL Extended Release Tablets in 21 males with type 2 diabetes and patients younger than 65 years. Approximately 1 to 2 days longer were required to reach steady-state in 24 elderly (≥65 years) males and females with type 2 diabetes. No accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with GLUCOTROL XL Extended Release Tablets. Administration of GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of GLUCOTROL XL immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean Cmax value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the GLUCOTROL XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with type 2 diabetes, the pharmacokinetics of glipizide were linear over the dose range of 5 to 60 mg of GLUCOTROL XL in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects, four 5-mg, two 10-mg, and one 20-mg GLUCOTROL XL Extended Release Tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg GLUCOTROL XL Extended Release Tablets were bioequivalent to one 10-mg GLUCOTROL XL Extended Release Tablet. Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts for less than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes. The mean apparent volume of distribution was approximately 10 liters. Glipizide is 98–99% bound to serum proteins, primarily to albumin. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes. There were no significant differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects compared to younger healthy subjects. There is only limited information regarding the effects of renal impairment on the disposition of glipizide, and no information regarding the effects of hepatic disease. However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with renal or hepatic impairment. In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug |
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| 药物动力学和新陈代谢：Glipizide 快速地而且完全地被吸收的立即版本的下列的口服行政剂量形式。glipizide 的绝对生物药效在单一口服剂量之后在患有 2 型糖尿病的患者是 100%了。开始 2-3 小时在 GLUCOTROL XL 的行政之后延长了版本锭剂，血浆药物浓度在 6-12 小时之内在配之后逐渐地上升达成最大浓度。与后来的一经每日 GLUCOTROL XL 的配延长了版本锭剂，有效的血浆 glipizide 浓度到处被维护配间隔的 24 小时与比较不最高对木钵变动超过哪一观察与两次每日立即版本 glipizide 的配。在患有 2 型糖尿病的 21个男性中的 glipizide 的平均相对生物药效在 20 毫克 GLUCOTROL XL 的行政之后延长了与立即的版本 Glucotrol（每日被给予两次的 10 毫克）相较的版本锭剂是 90% 在不变的。不变的血浆浓度在至少第五天─在患有 2 型糖尿病的 21个男性中有 GLUCOTROL XL 广大的版本锭剂配之前被达成了和患者比 65 年年轻。大约长 1-2 天为到达所需不变的在 24个年老的 （≥ 65 年）男性和患有 2 型糖尿病的女性中。药物的没有蓄积在慢性的配期间以被延长版本锭剂的 GLUCOTROL XL 在患有 2 型糖尿病的患者中被观察。GLUCOTROL XL 的行政用食物在药物吸收中对 2-3 小时延迟时间产生没有影响。在一个剂量中，食物效果在 21个健康男性主题中学习， GLUCOTROL XL 的行政立刻在一之前高的脂肪早餐造成 glipizide 的40%增加平均数 Cmax 数值，这是重要的，但是对 AUC 的影响不重要。没有葡萄糖方面的改变响应在这之间喂和禁食状态。显着地减少在延长的期数 （举例来说，短肠征候群）上的 GI 滞留 GLUCOTROL XL 锭剂的时代可能影响药物的药物动力描绘而且可能地造成较低的血浆浓度。在患有 2 型糖尿病的 26个男性中的一项多项剂量研究中， glipizide 的药物动力学在血浆药物浓度相称地，以剂量增加的 5-60 毫克 GLUCOTROL XL 的剂量范围之上是线性的。在剂量 24个健康主题中的研究中，四 5 毫克，二 10 毫克，和 20 毫克 GLUCOTROL XL 广大的版本锭剂是 bioequivalent。在 36个健康主题的一项分开的单一剂量研究中，四 2.5 毫克 GLUCOTROL XL 广大的版本锭剂是 bioequivalent 至 10 毫克 GLUCOTROL XL 延长版本锭剂。Glipizide 主要地被肝的生物转化所除去：少于 10% 的一个剂量在尿液和粪便中当做不变的药物被排泄；大约 90% 的一个剂量在尿液 （80%) 和粪便 （10%) 中当做生物转化产品被排泄。glipizide 的主要新陈代谢产物是芬芳羟化的产品而且没有血糖过低的活动。一个占有小于 2% 的一个剂量，一个 acetylamino－乙基苯的衍生物，的较小的新陈代谢产物被指出有 1|10-1|3 像母化合物一样的多血糖过低的活动。glipizide 的平均完全身体净空大约是患有 2 型糖尿病的患者中的单一静脉注射的剂量后的每小时 3个升。分配的平均表观重量大约是 10个升。Glipizide 是对血清蛋白质约束的 98-99%，主要地对蛋白素。glipizide 的平均终末排除半生期在单一或多重剂量之后在患有 2 型糖尿病的患者从 2 排列到 5 小时了。与比较年轻的健康主题相较对旧的糖尿病的主题没有在单一剂量行政后的 glipizide 的药物动力学中的重要不同。关于肾损害对 glipizide 的素质的效果、和没有关于肝疾病的效果的信息只有有限制的信息。然而，因为 glipizide 是高度蛋白质的界线，而且肝的生物转化是排除的优越路径， glipizide 的药物动力学和│或者药效学可能在患者中被肾或肝的损害所改变。在老鼠没有 glipizide 或新陈代谢产物中是脑或男性或女性的脊髓中的可发觉的 autoradiographically，也不在怀孕女性的胎儿中。在另外的一项研究中，然而，非常小量放射性在给定的鼠的胎儿中被发现贴上标签药物 |
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6楼2011-03-18 09:41:33