|
| Distribution |
药物分布 |
| After a drug enters the systemic circulation, it is distributed to the body's tissues. Distribution is generally uneven because of differences in blood perfusion, tissue binding, regional pH, and permeability of cell membranes. |
药物进入体循环后分布于机体各组织。由于血液灌注差异、组织结合力、局部pH值和细胞膜通透性差异等的不同，药物分布一般也是不均匀的。 |
| The entry rate of a drug into a tissue depends on the rate of blood flow to the tissue, on tissue mass, and on partition characteristics between blood and tissue. Distribution equilibrium （when entry and exit rates are the same） between blood and tissue is reached more rapidly in richly vascularized areas than in poorly perfused areas, unless diffusion across membrane barriers is the rate-limiting step. After equilibrium is attained, drug concentrations in tissues and in extracellular fluids are reflected by the plasma concentration. Metabolism and excretion occur simultaneously with distribution, making the process dynamic and complex. |
药物进入组织的速率取决于血流进入该组织的速率，取决于组织质量及药物在血液与组织间的分配特性。在透过细胞膜屏障的弥散作用未成为限速步骤的条件下，血管丰富的区域达到血液与组织间分布平衡（即药物进入率和离开率相等）的速率要快于血液灌注差的区域。达到分布平衡后，便可通过血浆浓度反映组织和细胞外液的药物浓度。代谢和排泄与药物分布同时进行，分布由此成为一个复杂的动态过程。 |
| Apparent Volume of Distribution |
表观分布容积 |
| The volume of fluid into which a drug appears to be distributed or diluted is called the apparent volume of distribution （the fluid volume required to contain the drug in the body at the same concentration as in plasma）. This parameter provides a reference for the plasma concentration expected for a given dose and for the dose required to produce a given concentration. However, it provides little information about the specific pattern of distribution. Each drug is uniquely distributed in the body. Some drugs go into fat, others remain in the ECF, and still others are bound avidly to specific tissues, commonly liver or kidney. |
药物分布进入或得以稀释的液体容积量被称为表观分布容积（维持机体药物浓度与血浆药物浓度相等所需要的液体容积）。该参数可以为预期一次剂量后的血浆浓度以及预计达到某个血药浓度所需要的剂量提供参考。然而，表观分布容积并不能提供特定的分布类型信息。每种药物在体内的分布都是独一无二的。一些药物分布于脂肪；另外一些药物则停留于细胞外液；还有一些药物则牢固地与一些特殊组织结合，通常是肝脏和肾脏。 |
| Many acidic drugs （eg, warfarin, salicylic acid） are highly protein-bound and thus have a small apparent volume of distribution. Many basic drugs （eg, amphetamine, meperidine） are avidly taken up by tissues and thus have an apparent volume of distribution larger than the volume of the entire body. |
许多酸性药物（如华法林和水杨酸）与蛋白质结合度高，因此表观分布容积小。许多碱性药物（如苯丙胺和哌替啶）极易被组织摄取，因此，其分布容积比整个身体的容积还要大。 |
| Binding |
结合 |
| The extent of drug distribution into tissues depends on the extent of plasma protein and tissue binding. |
药物分布进入组织的程度取决于与血浆蛋白和组织的结合程度。 |
| Plasma protein binding: Drugs are transported in the bloodstream partly in solution as free （unbound） drug and partly bound to blood components （eg, plasma proteins, blood cells）. The ratio of bound to unbound drug in plasma is mainly determined by the reversible interaction between a drug and the plasma protein to which it binds, as governed by the law of mass action. Many plasma proteins can interact with drugs. Albumin,α1-acid glycoprotein, and lipoproteins are most important. Acidic drugs are generally bound more extensively to albumin, and basic drugs toα1-acid glycoprotein and/or lipoproteins. |
血浆蛋白结合 药物在血流中转运时，一部分是以游离药溶解于血液中（非结合型），另一部分则与血液成分（如血浆蛋白、血细胞）相结合。结合与非结合药物在血浆中的比率主要是由药物分子和血浆蛋白质分子间的可逆性相互作用决定，并受质量作用定律支配。多种血浆蛋白都能与药物发生相互使用。白蛋白、α1-酸性糖蛋白和脂蛋白最重要。酸性药物与白蛋白结合较广泛，碱性蛋白则与α1-酸性糖蛋白和脂蛋白结合更多。 |
| Only unbound drug is thought to be available for passive diffusion to extravascular or tissue sites where pharmacologic effects occur. Therefore, the unbound drug concentration may be more closely related to drug concentration at the active site and to drug effects, often making the fraction unbound （ratio of unbound to total concentrations） a more useful parameter than the fraction bound. Plasma protein binding influences distribution and the apparent relationship between pharmacologic activity and total plasma drug concentration. At high drug concentrations, the amount of bound drug approaches an upper limit depending on the number of available binding sites, resulting in saturability. Saturability is the basis of displacement interactions among drugs. |
一般认为，只有非结合药物才能通过被动扩散到达产生药理作用的血管外或组织部位，因此，非结合型药物浓度和药物效应以及和作用部位的药物浓度关系更密切。非结合型分数（非结合型药物浓度与总药物浓度之比）这一参数常比结合型分数更有用。血浆蛋白的结合作用会影响药物的分布，并影响药理活性和总血浆药物浓度间的表观关系。药物浓度高时，因蛋白可结合部位数目的关系，结合药物量接近上限，导致饱和性。饱和性是药物间相互置换作用的基础。 |
| Tissue binding: Drugs bind to many substances other than proteins. Binding may be very specific, as when chloroquine binds with nucleic acids. Binding usually occurs when a drug associates with a macromolecule in an aqueous environment but may occur when a drug is partitioned into body fat. Because fat is poorly perfused, equilibration time is long, especially if the drug has a high affinity for fat. |
组织结合 除蛋白质外，药物还可以和其他许多物质结合。结合可能是极其特异性的，如氯喹与核酸类结合。药物的结合常在水相环境中与大分子结合，也可在药物进入脂肪组织时发生。由于脂肪组织的血液灌注差，达到平衡状态所需的时间也长，特别是那些脂肪亲和力高的药物。 |
| Drug reservoir: Accumulation of drugs in tissues or body compartments can prolong the sojourn of drug in plasma and drug action because the tissues release stored drug as the plasma concentration declines. Location of the active site and relative differences in tissue distribution can also be important. For the anesthetic thiopental, storage in tissue reservoirs initially shortens the drug effect but after repeated administration prolongs it. |
药物储库 药物在组织或机体腔室的积聚能延长药物在血浆中的逗留时间，从而延长药物作用时间，这是因为，当血浆药物浓度下降时，组织就会把贮存药物释放出来。起效部位的位置和组织分布的相对差异性也可能很重要。如麻醉药硫贲妥，它贮存于组织储库中，开始时会缩短药物的效应期，但经多次给药后就会使之延长。 |
| Thiopental is highly lipid soluble and rapidly distributes to the brain after a single IV injection. After a single dose, thiopental concentration in the brain increases for a few minutes, then declines parallel with the plasma concentration. Anesthesia ends rapidly as the drug redistributes to more slowly perfused tissues. However, if plasma concentration is monitored long enough, a third phase of distribution, in which the drug is slowly released from fat, can be distinguished. With continued administration of thiopental, large amounts may be stored in fat, resulting in prolongation of anesthetic plasma concentrations. |
硫贲妥是高脂溶性药物，单次静注后就会迅速分布进入脑组织。单次静注后，脑内硫贲妥浓度就会增加，并达几分钟。接着就开始下降，其速度与血浆浓度下降相对应。当药物再分布于灌注更慢的组织时，麻醉迅速终止。不过，如果血浆浓度监测时间够长的话，你就会发现药物分布的第三相，此时，药物便缓慢地从脂肪组织释放出来。如果连续使用硫贲妥，大量药物就会被贮存于脂肪组织内，结果是延长麻醉药血浆浓度时间。 |
| Some drugs accumulate, producing higher concentrations in cells than in ECF, most commonly because they bind with protein, phospholipids, or nucleic acids. Antimalarial drugs （eg, chloroquine） produce concentrations within WBCs and liver cells thousands of times higher than those in plasma. The stored drug is in equilibrium with drug in plasma and moves into plasma as the drug is eliminated from the body. |
某些药物在细胞内积聚，使细胞内浓度高于细胞外液浓度，最常见的原因是他们与蛋白质、磷脂或核酸的结合。抗疟药（如氯喹）在白细胞内和肝细胞内的浓度要比血浆中的浓度高出数千倍。贮存药物与血浆处于平衡状态，当药物由机体消除时，贮存药物即进入血浆。 |
| Blood-Brain Barrier |
血脑屏障 |
| Drugs reach the CNS via brain capillaries and via CSF. Although the brain receives about 1/6 of cardiac output, distribution of drugs to brain tissue is restricted. Some lipid-soluble drugs （eg, thiopental） enter the brain and exert their pharmacologic effects rapidly, but many drugs, particularly the more water-soluble drugs, enter the brain slowly. The endothelial cells of the brain capillaries, which appear to be more tightly joined to one another than are those of other capillaries, contribute to the slow diffusion of water-soluble drugs. |
药物经脑毛细血管和脑脊液进入中枢神经系统。虽然脑部接收了约1/6的心输出量，但药物向脑组织的分布仍受到一定的限制。有些脂溶性药物（如硫贲妥）能很快进入脑组织并发挥其药理作用。但其他很多药物，特别是水溶性较高的药物，进入脑部很慢。脑部毛细血管内皮细胞的相互联接比其他部位毛细血管的更紧密，放缓水溶性药物的扩散。 |
| Another barrier to water-soluble drugs is the glial connective tissue cells （astrocytes）, which form an astrocytic sheath close to the basement membrane of the capillary endothelium. The capillary endothelium and the astrocytic sheath form the blood-brain barrier. Because the capillary wall rather than the parenchymal cell forms the barrier, the brain's permeability characteristics differ from those of other tissues. Thus, polar compounds cannot enter the brain but can enter the interstitial fluids of most other tissues. The observation that polar dyes enter most tissues but not the CNS led to the concept of the blood-brain barrier. |
水溶性药物的另一个屏障是胶质结缔组织细胞（星形细胞），该细胞所形成的星形细胞鞘与毛细血管内皮基膜紧密邻接。毛细血管内皮和星形细胞鞘一起构成血脑屏障。由于这一屏障是由毛细血管壁构成，并非实质细胞，因此，脑组织的渗透性特征也不同于其他组织。这样，极性物质就不能进入脑组织，但可以进入其他多数组织间液。极性染料能进入多数组织而不能进入中枢神经系统，这一观察结果导致“血脑屏障”概念的出现。 |
| Drugs may enter ventricular CSF directly via the choroid plexus, entering brain tissue by passive diffusion from CSF. Also in the choroid plexus, organic acids （eg, penicillin） are actively transported from CSF to blood. |
药物可经由脉络丛直接进入侧脑室脑脊液，再经被动扩散由脑脊液进入脑组织。此外，在脉络丛中，有机酸类（如青霉素）从脑脊液经主动转运到血液中。 |
| The drug penetration rate into the CSF or into other tissue cells is determined mainly by the extent of protein binding, the degree of ionization, and the lipid-water partition coefficient of the drug. The penetration rate into the brain is slow for highly protein-bound drugs and can be so slow for the ionized form of weak acids and bases as to be virtually nonexistent. |
药物进入脑脊液或其他组织的通透速率主要由药物的下列因素决定：与蛋白质的结合程度、解离度、以及脂-水分配系数。高度蛋白结合药物的入脑通透速率缓慢，慢得使解离型弱酸或弱碱的通透速率几乎为零。 |
| Because the CNS is so well perfused, permeability is generally the major determinant of the drug distribution rate. However, for the interstitial fluids of most tissues, perfusion is a major determinant. For poorly perfused tissues （eg, muscle, fat）, distribution is very slow, especially if the tissue has a high affinity for the drug. |
中枢神经系统的血液灌注极佳，一般说来，通透性是药物分布速率的主要决定因素。不过，对大多数组织的间液来说，血液灌注是主要决定因素。血液灌注差的组织（如肌肉、脂肪）的分布过程非常缓慢，特别是当该组织对药物具有很高的亲和性时。 |
|
