| Distribution | 藥物分布 |
| 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. | 藥物進(jìn)入體循環(huán)后分布于機(jī)體各組織。由于血液灌注差異、組織結(jié)合力、局部pH值和細(xì)胞膜通透性差異等的不同，藥物分布一般也是不均勻的?！?/td> |
| 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. | 藥物進(jìn)入組織的速率取決于血流進(jìn)入該組織的速率，取決于組織質(zhì)量及藥物在血液與組織間的分配特性。在透過細(xì)胞膜屏障的彌散作用未成為限速步驟的條件下，血管豐富的區(qū)域達(dá)到血液與組織間分布平衡（即藥物進(jìn)入率和離開率相等）的速率要快于血液灌注差的區(qū)域。達(dá)到分布平衡后，便可通過血漿濃度反映組織和細(xì)胞外液的藥物濃度。代謝和排泄與藥物分布同時(shí)進(jìn)行，分布由此成為一個(gè)復(fù)雜的動(dòng)態(tài)過程?！?/td> |
| Apparent Volume of Distribution | 表觀分布容積 |
| 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. | 藥物分布進(jìn)入或得以稀釋的液體容積量被稱為表觀分布容積（維持機(jī)體藥物濃度與血漿藥物濃度相等所需要的液體容積）。該參數(shù)可以為預(yù)期一次劑量后的血漿濃度以及預(yù)計(jì)達(dá)到某個(gè)血藥濃度所需要的劑量提供參考。然而，表觀分布容積并不能提供特定的分布類型信息。每種藥物在體內(nèi)的分布都是僅有的。一些藥物分布于脂肪；另外一些藥物則停留于細(xì)胞外液；還有一些藥物則牢固地與一些特殊組織結(jié)合，通常是肝臟和腎臟?！?/td> |
| 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. | 許多酸性藥物（如華法林和水楊酸）與蛋白質(zhì)結(jié)合度高，因此表觀分布容積小。許多堿性藥物（如苯丙胺和哌替啶）極易被組織攝取，因此，其分布容積比整個(gè)身體的容積還要大?！?/td> |
| Binding | 結(jié)合 |
| The extent of drug distribution into tissues depends on the extent of plasma protein and tissue binding. | 藥物分布進(jìn)入組織的程度取決于與血漿蛋白和組織的結(jié)合程度?！?/td> |
| 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. | 血漿蛋白結(jié)合 藥物在血流中轉(zhuǎn)運(yùn)時(shí)，一部分是以游離藥溶解于血液中（非結(jié)合型），另一部分則與血液成分（如血漿蛋白、血細(xì)胞）相結(jié)合。結(jié)合與非結(jié)合藥物在血漿中的比率主要是由藥物分子和血漿蛋白質(zhì)分子間的可逆性相互作用決定，并受質(zhì)量作用定律支配。多種血漿蛋白都能與藥物發(fā)生相互使用。白蛋白、α1-酸性糖蛋白和脂蛋白最重要。酸性藥物與白蛋白結(jié)合較廣泛，堿性蛋白則與α1-酸性糖蛋白和脂蛋白結(jié)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. | 一般認(rèn)為，只有非結(jié)合藥物才能通過被動(dòng)擴(kuò)散到達(dá)產(chǎn)生藥理作用的血管外或組織部位，因此，非結(jié)合型藥物濃度和藥物效應(yīng)以及和作用部位的藥物濃度關(guān)系更密切。非結(jié)合型分?jǐn)?shù)（非結(jié)合型藥物濃度與總藥物濃度之比）這一參數(shù)常比結(jié)合型分?jǐn)?shù)更有用。血漿蛋白的結(jié)合作用會(huì)影響藥物的分布，并影響藥理活性和總血漿藥物濃度間的表觀關(guān)系。藥物濃度高時(shí)，因蛋白可結(jié)合部位數(shù)目的關(guān)系，結(jié)合藥物量接近上限，導(dǎo)致飽和性。飽和性是藥物間相互置換作用的基礎(chǔ)?！?/td> |
| 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. | 組織結(jié)合 除蛋白質(zhì)外，藥物還可以和其他許多物質(zhì)結(jié)合。結(jié)合可能是極其特異性的，如氯喹與核酸類結(jié)合。藥物的結(jié)合常在水相環(huán)境中與大分子結(jié)合，也可在藥物進(jìn)入脂肪組織時(shí)發(fā)生。由于脂肪組織的血液灌注差，達(dá)到平衡狀態(tài)所需的時(shí)間也長，特別是那些脂肪親和力高的藥物?！?/td> |
| 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. | 藥物儲(chǔ)庫 藥物在組織或機(jī)體腔室的積聚能延長藥物在血漿中的逗留時(shí)間，從而延長藥物作用時(shí)間，這是因?yàn)?，?dāng)血漿藥物濃度下降時(shí)，組織就會(huì)把貯存藥物釋放出來。起效部位的位置和組織分布的相對差異性也可能很重要。如麻醉藥硫賁妥，它貯存于組織儲(chǔ)庫中，開始時(shí)會(huì)縮短藥物的效應(yīng)期，但經(jīng)多次給藥后就會(huì)使之延長?！?/td> |
| 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. | 硫賁妥是高脂溶性藥物，單次靜注后就會(huì)迅速分布進(jìn)入腦組織。單次靜注后，腦內(nèi)硫賁妥濃度就會(huì)增加，并達(dá)幾分鐘。接著就開始下降，其速度與血漿濃度下降相對應(yīng)。當(dāng)藥物再分布于灌注更慢的組織時(shí)，麻醉迅速終止。不過，如果血漿濃度監(jiān)測時(shí)間夠長的話，你就會(huì)發(fā)現(xiàn)藥物分布的第三相，此時(shí)，藥物便緩慢地從脂肪組織釋放出來。如果連續(xù)使用硫賁妥，大量藥物就會(huì)被貯存于脂肪組織內(nèi)，結(jié)果是延長麻醉藥血漿濃度時(shí)間。 |
| 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. | 某些藥物在細(xì)胞內(nèi)積聚，使細(xì)胞內(nèi)濃度高于細(xì)胞外液濃度，最常見的原因是他們與蛋白質(zhì)、磷脂或核酸的結(jié)合。抗瘧藥（如氯喹）在白細(xì)胞內(nèi)和肝細(xì)胞內(nèi)的濃度要比血漿中的濃度高出數(shù)千倍。貯存藥物與血漿處于平衡狀態(tài)，當(dāng)藥物由機(jī)體消除時(shí)，貯存藥物即進(jìn)入血漿?！?/td> |
| Blood-Brain Barrier | 血腦屏障 |
| 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. | 藥物經(jīng)腦毛細(xì)血管和腦脊液進(jìn)入中樞神經(jīng)系統(tǒng)。雖然腦部接收了約1/6的心輸出量，但藥物向腦組織的分布仍受到一定的限制。有些脂溶性藥物（如硫賁妥）能很快進(jìn)入腦組織并發(fā)揮其藥理作用。但其他很多藥物，特別是水溶性較高的藥物，進(jìn)入腦部很慢。腦部毛細(xì)血管內(nèi)皮細(xì)胞的相互聯(lián)接比其他部位毛細(xì)血管的更緊密，放緩水溶性藥物的擴(kuò)散?！?/td> |
| 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. | 水溶性藥物的另一個(gè)屏障是膠質(zhì)結(jié)締組織細(xì)胞（星形細(xì)胞），該細(xì)胞所形成的星形細(xì)胞鞘與毛細(xì)血管內(nèi)皮基膜緊密鄰接。毛細(xì)血管內(nèi)皮和星形細(xì)胞鞘一起構(gòu)成血腦屏障。由于這一屏障是由毛細(xì)血管壁構(gòu)成，并非實(shí)質(zhì)細(xì)胞，因此，腦組織的滲透性特征也不同于其他組織。這樣，極性物質(zhì)就不能進(jìn)入腦組織，但可以進(jìn)入其他多數(shù)組織間液。極性染料能進(jìn)入多數(shù)組織而不能進(jìn)入中樞神經(jīng)系統(tǒng)，這一觀察結(jié)果導(dǎo)致“血腦屏障”概念的出現(xiàn)。 |
| 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. | 藥物可經(jīng)由脈絡(luò)叢直接進(jìn)入側(cè)腦室腦脊液，再經(jīng)被動(dòng)擴(kuò)散由腦脊液進(jìn)入腦組織。此外，在脈絡(luò)叢中，有機(jī)酸類（如青霉素）從腦脊液經(jīng)主動(dòng)轉(zhuǎn)運(yùn)到血液中?！?/td> |
| 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. | 藥物進(jìn)入腦脊液或其他組織的通透速率主要由藥物的下列因素決定：與蛋白質(zhì)的結(jié)合程度、解離度、以及脂-水分配系數(shù)。高度蛋白結(jié)合藥物的入腦通透速率緩慢，慢得使解離型弱酸或弱堿的通透速率幾乎為零。 |
| 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. | 中樞神經(jīng)系統(tǒng)的血液灌注極佳，一般說來，通透性是藥物分布速率的主要決定因素。不過，對大多數(shù)組織的間液來說，血液灌注是主要決定因素。血液灌注差的組織（如肌肉、脂肪）的分布過程非常緩慢，特別是當(dāng)該組織對藥物具有很高的親和性時(shí)?！?/td> |
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