药代

Advanced Medicinal Chemistry
Lecture 5:
Drug Metabolism and Pharmokinetics - 2
药物代谢及 药代动力学
Barrie Martin AstraZeneca R&D Charnwood 阿斯利康是一家以创新为 驱动的全球性生物制药企业
Time The volume of distribution (VD) is therefore:
When the volume doubles (red line), the initial concentration halves and the half life doubles
In biological systems, compounds can distribute out of the plasma into tissues. The theoretical volume (L) that all the drug in the body would have to occupy if it were present at the same concentration as that found in plasma. It is a measure of how readily drug diffuses out of the plasma into the tissues and can affect t 1/2. – Low VD: drug confined to plasma (vulnerable to the liver and metabolism) – High VD: drug equilibrates with tissues
单位时间消除的量 dD/dt
Cx =
Ux(尿中浓度)×V(每分尿量) Px(血中浓度)
Clearance (Cl)
Over a small interval of time, dt:
Amount eliminated during interval dt = Cl x Conc x dt
Integrating this over the whole concentration-time profile gives:
Cl = E x Q (E = extraction ratio)
If Cl ~ Q (i.e. E~1), then 1st pass metabolism is a likely problem.
The precise equation is:
t1/2 = 0.693 x VD/Cl
Clearance, Volume and Half-Life
Half-life is not predictable from clearance alone - clearance characterises elimination of drug from plasma/blood - half-life also depends on distribution of drug outside the plasma (systemic circulation not a closed system) For a rapid (bolus) iv dose; where D is the amount of drug in the body at time t;
Rate ofh elimination,
But D = VD x concentration, so kel x VD = Cl 0.693 kel
dD = kelD = Clearance x concentration dt or kel = Cl VD
Rem:
t1/2
=
,
t1/2 =
0.693 x VD Cl
NB: t½ is NOT a measure of how rapidly the drug is metabolised
注:t½ 不是衡量药物生物新陈代谢的速度
Clearance, Extraction and Absorption
For the three main elimination processes, metabolism, renal, and biliary, clearances are additive, i.e.
Plasma conc
x x x x
-kelt C = Coe
ln c
x
ln c = ln co - kelt
x
x
x
- kel = slope x x x
x
Time
Time
Under first order kinetics, rate of metabolism is proportional to the compound concentration, so the rate (and gradient) decr eases over time. By plotting ln c vs. time, we can determine the elimination rate constant (k el) from the slope of the line and, by extrapolation back to t = 0, the initial plasma concentration c 0. The main use of kel is to determine the half-life (t1/2) of the compound, defined as: The time taken for the concentration of drug in the blood or plasma to decline ቤተ መጻሕፍቲ ባይዱo half of its original value.
Clearance (Cl)
Clearance (Cl) is a measure of how readily compounds are eliminated (i.e. metabolised or excreted) It is defined as:
清除率
代谢和排泄
The volume of plasma (or blood) from which all drug is removed per unit time. (n.b. units of Cl are units of flow ml/min) Cl is a constant, characteristic of a drug in a particular species. It is a scaling factor that relates the plasma concentrat ion of a compound to the rate of elimination Rate of elimination (ng/min) = Clearance x concentration (ng/ml)
ClT = ClM + ClR + ClB
新陈代谢,肾,和胆汁
e.g. If ClT = 20ml/min/Kg and %dose as parent in urine = 20% Then ClR = 4ml/min/Kg
Can relate clearance to liver blood flow (Q):
涉及大量的药代动力学参数的测量
用于化合物之间的对比， 反应化合物的不足， 预测潜在药物作用于人类
The One Compartment Model
一室模型
The simplest model to describe the fate of a compound in the body is the ‘one compartment model’, which is analogous to the metabolism of the compound in a beaker containing an enzyme solution. Although simplistic, many of the basic parameters of pharmacokinetics (half-life, clearance and volume of distribution) are well illustrated using this model.
Generally: Acids - high PPB, low VD
Neutrals - ready equilibration, but not necessarily retained in the tissue - higher VD
Bases - high affinity for phospholipids in membranes (negatively charged) - highest VD
Quantitative DMPK
Quantitative DMPK involves the measurement of a number of pharmacokinetic parameters which describe the fate of compounds in the body.
These can be used to compare compounds, to highlight deficiencies in compounds (e.g. high metabolism) and to predict how the potential drug will behave in man – generate dose predictions.
半衰期,清除和分布容积
Injection
BLOOD
半衰期
Half-Life (T1/2) and the Elimination Rate Constant (kel)
消除速率常数
Following an iv injection, we might expect the plasma concentration of a compound to vary over time as shown below:
( dD ) dt

Rate of elimination (ng/min)
Clearance (ml/min) = concentration (ng/ml)
• 一、概念及计算方法 • 两肾在单位时间(1 min)内，能将多
• • • 少毫升血浆中的某物质完全清除出去， 这个被完全清除了该物质的血浆毫升数， 称为该物质的清除率。
Plasma Conc
CL= dD/dt C
dD/dt=kelD
dt
Total amount eliminated = Dose = Cl x AUC Cl = Dose/AUC -kelt C = Coe
Conc
∫
Time
t 0 Cdt
kel = Conc. x Cl
Clearance is related to t1/2 and VD. If Cl halves, then the half life doubles (because the rate of metabolism halves) and, as we have seen, doubling the volume doubles the half-life (because the concentration at the metabolising enzyme has halved).
At t1/ ,
2
c 1 = co 2
ln (0.5) = - kel t1/ , 2
t1/ = 0.693 2
kel
Volume of Distribution (VD)
ln c
分布容积
Consider now the case where a compound is dissolved in double the volume, what would happen to t1/2?