Section Ⅵ. Section Ⅵ. Pharmacological Pharmacological

Basis of Basis of TherapeuticsTherapeutics药物治疗学基础药物治疗学基础

浙江大学医学院基础医学系 •汤慧芳

Chapter 2Pharmacokinetics

Part 1. Drug transportation across cell membranePart 2. The process of drug in bodyPart 3. Pharmacokinetics process

Part 1. Drug transportation across cell membrane

1. Classification of 1. Classification of pharmacokinetics process (pharmacokinetics process ( 药药动学过程的分类动学过程的分类 ))

①①Absorption(Absorption( 吸收吸收 )) ② ②Distribution(Distribution( 分布分布 )) ③ ③Biotransformation(Biotransformation( 生物转化生物转化 )) ④ ④Excretion(Excretion( 排泄排泄 )) ① ① + ② + ④ = transportation(+ ② + ④ = transportation( 转运转运 ) ) ③ ③ + ④ = elimination(+ ④ = elimination( 消除消除 )) ② ② + ③ + ④ = disposition(+ ③ + ④ = disposition( 处置处置 ))

2. Transportation of drugs (药物的转运 )The patterns of drug transportation across cell membrane:

Mechanisms of drug permeation A: filtration: tight junctions B: lipid diffusion: through lipid cell membranes C: carrier-mediated transport: transported by carriers into or out of cells D: membrane moving transport: endocytosis,and exocytosis.

3. Passive transportation(down 3. Passive transportation(down hill)hill)(1)Filtration(滤过 ) — along

pressure gradient)

(2)Simple diffusion(简单扩散 ) —

along concentration gradient)Characteristics of simple diffusion: ●need not carrier(不需要载体 ); ●don’t consume energy(不耗能 ); ●no saturation(无饱和现象 ); ●no competitive inhibition(无竞争性抑制 ); ●to dynamic equilibrium finally(最终保持在动态稳定水平 ).

The factors affecting simple diffusion● difference of drug concentration;

● lipid solubility of drug.

lipid solubility of drug ionizability of drug pKa of drug, and pH of solution. ion trapping(离子障 )

Handerson-Hasselbach’ Formula Weak acid drug: HA H+ + A–

[H+] [A–] Ka = [HA] [HA] [H+] = [A–] Ka log [HA] / [A–] = log [H+] – log Ka = pKa – pH When pH = pKa, [HA] = [A–] pH ＞ pKa, [HA] ＜ [A–] pH ＜ pKa, [HA] ＞ [A–]

log [HA] / [A– ] = pKa – pH Effect of pH on ionization of Salicyclic acid(水杨酸 , pKa=3)

pH log [HA] / [A–] [HA] / [A–] non-ionized(%) (pKa – pH) 1 3 – 1 = 2 100/1 99.0 2 3 – 2 = 1 10/1 90.0 3 3 – 3 = 0 1/1 50.0 4 3 – 4 = –1 1/10 10.0 5 3 – 5 = –2 1/100 1.0

6 3 – 6 = –3 1/1000 0.1

Fig. Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood. In the hypothetical case illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane, but the total concentration (charged plus uncharged) in the urine (more than 10 mg) is 25 times higher than in the blood (0.4 mg).

Weak base drug: BH+ H+ + B [B] [H+] Ka = [BH+] [B] Ka = [BH+] [H+] log [B] / [BH+] = log Ka – log [H+] = pH – pKa When pH = pKa, [B] = [BH+] pH ＞ pKa, [B] ＞ [BH+] pH ＜ pKa, [B] ＜ [BH+]

Clinical significance: ▲ 口服药物 , 在胃肠道吸收 , 弱酸性药物在酸性环境的胃中容易吸收 , 弱碱性药物在 pH 较高的肠道内容易被吸收 .

▲▲▲▲ 改变尿液的酸碱度可以影响药物在肾小管改变尿液的酸碱度可以影响药物在肾小管的重吸收过程的重吸收过程 . . 弱酸性药物在酸性尿液中容弱酸性药物在酸性尿液中容易重吸收易重吸收 , , 因此减少了该药物在尿液中的排因此减少了该药物在尿液中的排出出 , , 而弱酸性药物在碱性尿液中则重吸收减而弱酸性药物在碱性尿液中则重吸收减少少 , , 可增加该药物的排出量可增加该药物的排出量 ..

这一知识在临床上可以用于治疗某些药物这一知识在临床上可以用于治疗某些药物中毒中毒 . . 如催眠药苯巴比妥如催眠药苯巴比妥 (( 酸性药物酸性药物 )) 过量过量中毒时中毒时 , , 用用 NaHCONaHCO3 3 静脉滴注静脉滴注 , , 使尿液碱使尿液碱化化 , , 可减少苯巴比妥的重吸收而加速其排泄可减少苯巴比妥的重吸收而加速其排泄 ..

4. Active transportation(up hill)—— adverse concentration gradient transportation

Characteristics of active transportion:

●need carrier; ●energy consumption; ●saturability; ●competitive inhibition by

congeners; ●active transport stop when no

drug at one side of membrane.

Part 2. The process of drug in body

(1)Enteral ingestion(胃肠道给药 ) ●oral administration(per os, po) ▲Site of absorption ▲first-pass elimination(首过消除 ) ●sublingual(舌下含服 ) ●per rectum(直肠给药 )

(2)Parenteral administration ●Intravenous(iv) —— no absorption. ●Intramuscular(im), ●Subcutaneous(sc), ●Other administration ▲inhalation(吸入 ): aerosol; ▲transdermal administration(透皮给药 )

1. 1. Absorption Absorption

Factors affecting distribution:① Regional blood flow, redistribution② Physicochemical properties of drug: MW, LS, polarity, ③ Selectivity of drug distribution: e.g. iodine(碘 ) thyroid(甲状腺 )④ Biological barriers Blood-brain barrier(血脑屏障 ) Placenta barrier(胎盘屏障 ) Blood-eye barrier(血眼屏障 )⑤ Plasma protein binding of drug

2. Distribution

Plasma protein binding rate(PBR, 血浆蛋白结合率 )

Free type Binding type

Free type: ● Activity, ● Can be transported.Binding type: ● Reversible; ● Inactive temporarily; ● Cannot pass through

membrane passively; ● Saturability and competition.

Phase I and phase II reactions, and direct elimination, in drug biodisposition. Phase II reactions may also precede phase I reactions.

3. Biotransformation(1)

3. Biotransformation(2)

3. Biotransformation(3) (1)Phase of biotransformation ●Phase I : Oxidation, Reduction, Hydrolysis Most case: inactivation or detoxification Some case: activation or toxicity activation : cortisone hydrocortisone phenacetin acetaminophen (非那西丁 ) (对乙酰氨基酚 ) toxicity : para-phenetidin (对氨基苯乙醚 )

●Phase II : Conjugation

with glucuronides, or glycine, or acetyl, or sulfate, et al. )

Solubility Excretion from kidney

(2)Hepatic microsomal enzymes(肝微粒体酶 , hepatic drug-metabolizing enzymes, 肝药酶 )

Cytochrome P450 enzymes(细胞色素P450), including oxidases, reduc-tases, hydrolases and conjugases.

The characteristics of P450:The characteristics of P450: ● ● low selectivity(low selectivity( 选择性低选择性低 );); ● ● high variability(high variability( 变异性大变异性大 ): ): ● ● Enzyme induction(Enzyme induction( 酶诱导酶诱导 ) ) & &

Enzyme inhibition( Enzyme inhibition( 酶抑酶抑制制 ).).

Enzyme induction(酶诱导 ) & Enzyme inducer(酶诱导剂 ) Phenobarbital(苯巴比妥 ), Rifampin(利福平 ), et al.

Enzyme inhibition(酶抑制 ) & Enzyme inhibitor(酶抑制剂 )

Chloramphenicol(氯霉素 ), Isoniazid(异烟肼 ), Cimetidine(西咪替丁 ), et al.

(3)Other drug metabolism enzyme:●Non-microsomal reductive enzymes (非微粒体还原酶 , in hepatic cell),

●Esterase(酯酶 , in plasma),●Acetification enzyme(乙酰化酶 , in cell liquid), et al.

4. Excretion (1)Renal excretion: (1)Renal excretion: includingincluding ● glomerular filtrationglomerular filtration,, ● tubular secretiontubular secretion,, ● tubular reabsorptiontubular reabsorption

factors influencing renal factors influencing renal excretionexcretion

urinary flowurinary flow, , urinary pH.urinary pH.

(2)Biliary excretion: tetracycline(四环素 ), rifampin (利福平 ), erythromycin(红霉素 )

★hepato-enteral circulation: digitoxin(洋地黄毒苷 )

(3)Other excretion routes: lung, saliva, milk, sweat, et

al.

Part 3. Part 3. Pharmacokinetics Pharmacokinetics process process (rate process)(rate process)

• 1. Concentration-time relationship ( 药物浓度 - 时间关系 , 时量关系 ) and concentration-time curve( 药物浓度 -时间曲线 , C-T curve, 时量曲线 )

• Tmax: 达峰时间 ,• Cmax: 高峰浓度 ,• AUC: 曲线下面积 (area under curve).

1. latent period 2. persistent period (持续期 ); 3. residual period (残留期 ) (潜伏期 );

Tmax (Tpeak) Tmax (Tpeak)

CmaxCmax

MTCMTC

2. Kinetics of drug elimination( —— 药物消除动力学速率类型 )

dC = - keCn

dt C : concentration t : time ke: constant of elimination

rate n=1: first-order kinetics elimination

n=0: zero-order kinetics elimination

FIGURE Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant and independent of concentration.

恒比消除恒比消除 恒量消除恒量消除

(1)First-order kinetics elimination (一级动力学消除 , 恒比消除 ) d C = – keC1 dt d C = – Ke C dt d C = – Kedt C Ct = C0 e- ket

log Ct = log C0 – ke/2.303 t

log Ct = log C0 - ke/2.303 t log C C log C0

0 t slope = -ke/2.303

0 t

log Ct = log C0 - ke/2.303 t t = 2.303 / ke (log C0 - log Ct)

if: Ct = ½C0: t½为半衰期 t½ = 2.303 / ke • log 2 = 0.693 / ke

ke = 0.693 / t½

① Constant fraction is eliminated per unit time; ② log C - t curve is a straight line, the slope is -ke/2.303 ;

③ t½(半衰期 ) is constant, =0.693/ke; (be continued)

④once input drug(A), after 5 t ½, 96% of A is eliminated.

t ½ surplusage(%) elimination(%)

0 100 0

1 50 50

2 25 75

3 12.5 87.25

4 6.25 93.75

5 3.125 96.875

6 1.5625 98.4375

7 0.78125 99.27875

(2)Zero-order elimination (零级动力学消除 , 恒量消除 )

d C C = - kC0

d t = - k0

d C = - k0 dt Ct = C0 – k0t 0 t

① Constant amount is eliminated at maximal capacity per unit time;

② C-t curve is a straight line, its slope is -k; ③ t½ is not constant. K t½ = C0―(½C0) = ½C0 = 0.5C0

t½= 0.5 C0/K

(3)Michaelis-Menten eliminationPhenytoin(苯妥英 ),Salicyclic acid(水杨酸 )… dC Vmax • C = – dt Km + C

When C is very low, Km＞＞ C: 一级动力学 dC Vmax • C = – = – Ke C dt Km

When C is very high, Km＜＜ C: 零级动力学 dC Vmax • C = – = – Vmax = – K0

dt C

3. 3. Pharmacokinetics model(Pharmacokinetics model( 药动学药动学

模型模型 ):):Compartment model(Compartment model( 房室模型房室模型 ))

(1)one-compartment model(1)one-compartment model

DrugDrug absorptionabsorption eliminationelimination

Log C one-compartment model 32 16 8 elimination curve

4

2 C = C0 e-Ket

1

0 1 2 3 4 5 6 t1/2

(2)(2)two-compartment modeltwo-compartment model

DrugDrug CentralCentral

compartmecompartmentnt

PeripheralPeripheral

compartmecompartmentnt

absorptionabsorption eliminationelimination

log C A Two-compartment model

C = Ae-t + Be-t

distribution curve

B elimination curve

0 t

4. Parameters of pharmacokinetics and their meanings

(1)AUC(2)Bioavailability(F);(2)Apparent volume of

distribution(Vd);

(3)Half-life time(t½).

(1)Area under the conentration-(1)Area under the conentration-time curve (AUCtime curve (AUC ，，曲线下面积 ))

AUCAUC 代表进入体循环的药物的相对量代表进入体循环的药物的相对量 , , 可由梯可由梯形法则求得形法则求得 , , 单位为 单位为 g/ml·min g/ml·min 或 或 mg/L·h.mg/L·h.

ttmaxmax

CCmaxmax

(2)Bioavailability((2)Bioavailability( 生物利用度生物利用度 , , FF ))Fraction of absorption(Fraction of absorption( 吸收分数吸收分数 ))F = A / D ×100%F = A / D ×100%

F = AUC(po)/AUC(iv)×100%F = AUC(po)/AUC(iv)×100%F = AUCF = AUC(( 供试药供试药 ))/AUC/AUC(( 对照药对照药 ))×100%×100%

Affected factors:Affected factors: Rate of Rate of

absorptionabsorption First pass elimination(p.o.)First pass elimination(p.o.)

Routes of administration, bioavailability,and general characteristics.

某药剂量相等的三种制剂的生物利用度比较某药剂量相等的三种制剂的生物利用度比较F(AUC)F(AUC) 相等相等 , , 但但 TmaxTmax与与 CmaxCmax 不等不等

(3)Apparent volume of distribution(表观分布容积 , Vd) A (mg) Vd = (L or L/kg) C (mg/L) F D Vd = C Vd ≈ 5L: 药物主要分布在血浆中 ; Vd = 10～ 20L: 分布在全身体液中 ; Vd ＞ 40L: 主要分布在组织器官中 ; Vd ＞ 100L: 集中分布在某个器官内 .

Vd值越小 , 排泄越快 , 体内存留时间越短 ; Vd值越大 , 排泄越慢 , 体内存留时间越长 .

(4)Half-life time(半衰期 , t½) t½ 是血浆药物浓度或体内药量下降一半(50%)所需要的时间 .

一级动力学 : lnCt = lnC0―Ket Ke t½ = lnC0―ln(½C0) C0 = ln ½C0 = ln2 = 0.693

t½= 0.693/Ke t½是个常数 .

零级动力学 : Ct = C0―Kt

K t½ = C0―(½C0) = ½C0 = 0.5C0

t½= 0.5 C0/K

t½ 是随药物浓度而变化 .

tt½½ 的意义的意义 ::

•• tt½½ 表示药物在体内消除的速度或者机体对药表示药物在体内消除的速度或者机体对药物消除的能力物消除的能力 ;;

• • 一次给药后一次给药后 , , 按一级动力学消除按一级动力学消除 , , 经过经过 55个个 tt½½ 体内体内 96%96% 以上的药物被消除以上的药物被消除 ;;

• • 同一类作用的药物可按照同一类作用的药物可按照 tt½½ 再进行分类再进行分类 , , 例如长效类、中效类、短效类等例如长效类、中效类、短效类等 ;;

• • 肝肾功能不良者肝肾功能不良者 , , 绝大多数药物的绝大多数药物的 tt½½ 会延会延长长 ..

5. multiple dosing( 多次给药 )

(( 稳态浓度稳态浓度 ))

0 t

(1)Multiple dosing repeated iv injection: (1)Multiple dosing repeated iv injection: log Clog C

(2)Change dose and not change interval:

log C

0 0 t t

(3) Change dose and interval :

log C

0 0 t t

(4) Loading dose (D L) log C 2 D = loading dose

2D

D

0 t

(5) Continuous iv injection at a constant ratelog C

0 t

Let's take a rest!