第二章药物代谢动力学 Pharmacokinetics

第二章药物代谢动力学Pharmacokinetics

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

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

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

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

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…

尿pH值对药物排泄的影响 苯巴比妥[弱酸性药] (狗) 苯丙胺 [弱碱性药] (人) 50 40 精神反应计分值 20 40 酸性尿（pH~5）碱性尿（pH~7）碱性尿 pH 7.8-8.0 清除率 (ml/min) 0 2 30 血浆药物浓度 1 mM 20 0 30 酸性尿 pH<7 尿排泄量 10 15 mmol/h 0 0 0 1 2 3 4 5 6 7 0 2 4 6 8 排尿（ml/min）

10 8 6 4 2 0 120 20 40 60 80 100 0 口服和静脉注射阿司匹林659mg后的时-量曲线血浆阿司匹林浓度 (mg/L) 时间（min）

MEC 血药浓度 C A B 时间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%

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血浆地高辛浓度 (nmol/L) 2 1 2 4 5 0 1 3 时间（h）

Elimination kinetics 1. First-order elimination kinetics

多次给药的时-量曲线 2 Css.max 药物浓度 Css.min 1 稳态浓度 0 1 0 2 7 3 4 5 6

A B C 血药浓度 300 300 300 MTC 200 200 200 100 MEC 100 100 0 0 0 0 6 0 6 0 6 4 8 8 8 2 2 4 2 4 时间（半衰期）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

2. Zero-order elimination kinetics

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

Gepirone is a 5-HT1A agonist for the treatment of major depression. • half-life of3 h and good oral bioavailability, and undergoes extensive first-pass metabolism

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.

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)

Figure 1. Mean gepirone plasma concentrationsfollowing 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).

Figure 2. Mean 1-PP plasma concentrations followingadministration 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).

第二章药物代谢动力学 Pharmacokinetics