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 Reservoirs

Bound

ExceretionAbsorption

Across membraneand lipid

Across aqueous channel

Carrier-mediated transport

Outside

Inside

Manners of Transport Across Membrance

Passive transport

Routes of Drug Administration

Enteral

within or by way of the GI tract Oral (PO), rectal, sublingual

Parenteral

Not within the alimentary canalInhalation, IM, SC, IP, topical

CentralInto the brain or spinal cordIntrathecal

Routes of Drug Administrationcommon 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…

清

除

率

(ml/

min

)

50

40

30

20

10

00 2 4 6 8

0

20

40

0

1

2

0

15

30

0 1 2 3 4 5 6 7

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 ）

mm

ol/h

m M

计 分 值

尿 pH 值对药物排泄的影响

0 20 40 60 80 100 120

0

2

4

6

8

10

血 浆 阿 司 匹 林 浓 度(m

g/L

)

时间（ min ）

口服和静脉注射阿司匹林 659mg 后的时 - 量曲线

时间

C

A

B

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%

血 浆 地 高 辛 浓 度(n

mol

/L)

1 2 3 4 50

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 ）

Elimination kinetics 1. First-order elimination

kinetics

0

2

1

0 1 2 3 4 5 6

稳态浓度

药 物 浓 度

Css.max

Css.min

7

多次给药的时 - 量曲线

血 药 浓 度

100

200

300

80 2 4 60 0

0 2 4 6 8

100

200

300

时间（半衰期）

100

200

300

0 2 4 60

A B C

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

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 of 3 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).