第二章 药物代谢动力学 Pharmacokinetics. Transformation Free Systemic Circulation Bound drug Free drug Metabolites Locus of Action “receptors” Bound Free Tissue.

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1 第二章 药物代谢动力学 Pharmacokinetics

2 Transformation Free Systemic Circulation Bound drug Free drug Metabolites Locus of Action “receptors” Bound Free Tissue Reservoirs Bound Exceretion Absorption

3 Across membrane and lipid Across aqueous channel Carrier- mediated transport Outside Inside Manners of Transport Across Membrance Passive transport

4 Routes of Drug Administration Enteral within or by way of the GI tract Oral (PO), rectal, sublingual Parenteral Not within the alimentary canal Inhalation, IM, SC, IP, topical Central Into the brain or spinal cord Intrathecal

5 Routes of Drug Administration common abbreviations… PO = per os = oral IV = intravenous = into the vein IM = intramuscular = into the muscle SC = subcutaneous = between the skin and muscle IP = intraperitoneal = within the peritoneal cavity icv = intracerebroventricular = directly into the ventricle of the brain

6 Factors Affecting Response to Drugs Dosage Route of Administration Rate of Absorption Rate of Elimination Physiochemical properties of the drug age, sex, species, metabolism, etc…

7 清 除 率 (ml/min) 50 40 30 20 10 0 02468 0 20 40 0 1 2 0 15 30 01234567 苯巴比妥 [ 弱酸性药 ] ( 狗 ) 苯丙胺 [ 弱碱性药 ] ( 人 ) 精神反应 血浆药物浓度 尿排泄量 酸性尿 （ pH~5 ） 碱性尿 （ pH~7 ） 碱性尿 pH 7.8-8.0 酸性尿 pH<7 排尿（ ml/min ） mmol/h mMmM 计分值计分值 尿 pH 值对药物排泄的影响

8 0 20406080100 120 0 2 4 6 8 10 血 浆 阿 司 匹 林 浓 度 (mg/L) 时间（ min ） 口服和静脉注射阿司匹林 659mg 后的时 - 量曲线

9 时间 C A B 血药浓度血药浓度 MEC 三种不同的生物利用度 A. 吸收速度快、吸收量完全 B. 吸收速度与 A 相同，但吸收量仅为 A 的 50% C. 吸收量完全，但吸收速度为 A 的 50%

10 血 浆 地 高 辛 浓 度 (nmol/L) 1 2 3 45 0 1 2 四种由不同药厂生产的相同剂量地高辛片剂的生物利用度 时间（ h ）

11 Elimination kinetics 1. First-order elimination kinetics

12 0 2 1 0 1 2 3456 稳态浓度 药物浓度药物浓度 Css.max Css.min 7 多次给药的时 - 量曲线

13 血药浓度血药浓度 100 200 300 8 0 24 6 0 0 0 24 6 8 100 200 300 时间（半衰期） 100 200 300 0 2 4 6 0 ABC 8 MTC MEC 三种不同给药方案对稳态浓度的影响 A. 缩短给药时间 B. 增加给药剂量 C. 负荷量给药

14 2. Zero-order elimination kinetics

15 Pharmacokinetic Evaluation of Gepirone Immediate-Release Capsules and Gepirone Extended-Release Tablets in Healthy Volunteers JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 9, SEPTEMBER 2003

16 Gepirone is a 5-HT 1A agonist for the treatment of major depression. half-life of 3 h and good oral bioavailability, and undergoes extensive first-pass metabolism

17 Because of its rapid absorption and short half-life, the gepirone-IR (immediate-release formulation) must be administered at least twice daily. This regimen results in high peak concentrations and marked peak-to- trough fluctuations in plasma concentrations.

18 These fluctuations may contribute to an increased incidence of adverse events, such as nausea, dizziness, headache, and somnolence, and have the potential to result in lower patient compliance and reduced effectiveness. extended-release gepirone formulation( ER ) immediate-release formulation(IR)

19 Figure 1. Mean gepirone plasma concentrations following administration of gepirone-IR formulations (10mgq12 h,n=12) or gepirone-ER formulations (ER-1: 20 mg q24 h, n=12; ER-2: 20 mg q24 h, n=12; ER-3: 25 mg q24 h, n=12).

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21 Figure 2. Mean 1-PP plasma concentrations following administration of gepirone-IR formulations (10 mg q12 h, n=12) or gepirone-ER formulations (ER- 1: 20 mg q24 h, n=12; ER-2: 20 mg q24 h, n=12; ER-3: 25 mg q24 h, n=12).

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