| Drug Bioavailability | 藥物生活利用度 |
| The physicochemical properties of a drug govern its absorptive potential, but the properties of the dosage form （which partly depend on its design and manufacture） can largely determine drug bioavailability. Differences in bioavailability among formulations of a given drug can have clinical significance. Thus, the concept of equivalence among drug products is important in making clinical decisions. Chemical equivalence refers to drug products that contain the same compound in the same amount and that meet current official standards; however, inactive ingredients in drug products may differ. Bioequivalence refers to chemical equivalents that, when administered to the same person in the same dosage regimen, result in equivalent concentrations of drug in blood and tissues. Therapeutic equivalence refers to drug products that, when administered to the same person in the same dosage regimen, provide essentially the same therapeutic effect or toxicity. Bioequivalent products are expected to be therapeutically equivalent. | 藥物的理化性質(zhì)決定著藥物的吸收潛能，但是，劑型的性質(zhì)（部分依賴于設(shè)計和制作工藝）也在很大程度上決定藥物的生物利用度，同一藥物的不同配方所存在的生物利用度差異具有臨床意義。因而，藥物產(chǎn)品的等效概念在臨床決策中也很重要?；瘜W等值是指藥物制品中含有等量的同一主藥并符合現(xiàn)行法定標準，而其中的非活性成分則可以不等。生物等效是指將化學等值的藥品以同樣的給藥方案給予同一個體，在血液和組織中出現(xiàn)相等的濃度。治療等效是指幾個藥物制品以同樣給藥方案給予同一個體，產(chǎn)生本質(zhì)上相同的治療效應(yīng)或毒性。生物等效制品具有治療學等效性。 |
| Sometimes therapeutic equivalence may be achieved despite differences in bioavailability. For example, the therapeutic index （ratio of the maximum tolerated dose to the minimum effective dose） of penicillin is so wide that moderate blood concentration differences due to bioavailability differences in penicillin products may not affect therapeutic efficacy or safety. In contrast, bioavailability differences are important for a drug with a relatively narrow therapeutic index. | 有時，盡管生物利用度不同，但仍可獲得治療學等效性。例如，青霉素的治療指數(shù)（最大耐受劑量與最小有效量之比）如此之大，以至于由青霉素制品生物利用度差異引起的中等血濃度差異可能不會影響治療功效和安全性。相反，對于治療指數(shù)相對狹窄的藥物來說，生物利用度的差異就很重要?！?/td> |
The physiologic characteristics and comorbidities of the patient also affect bioavailability.
Absorption rate is important because even when a drug is absorbed completely, it may be absorbed too slowly to produce a therapeutic blood level quickly enough or so rapidly that toxicity results from high drug concentrations after each dose. | 病人的生理特征和疾患時也會影響藥物的生物利用度.
吸收速率很重要。這是因為，即使某藥物被完全吸收，得如果吸收速率太慢就不能迅速達到治療所需的血藥濃度；吸收太快，則每劑用藥后又會因藥物濃度高而產(chǎn)生毒性?！?/td> |
| Causes of Low Bioavailability | 低生物利用度的原因 |
| When a drug rapidly dissolves and readily crosses membranes, absorption tends to be complete, but absorption of orally administered drugs is not always complete. Before reaching the vena cava, a drug must move down the GI tract and pass through the gut wall and liver, common sites of drug metabolism; thus, a drug may be metabolized （first-pass metabolism） before it can be measured in the systemic circulation. Many drugs have low oral bioavailability because of extensive first-pass metabolism. For such drugs （eg, isoproterenol, norepinephrine, testosterone）, extraction in these tissues is so extensive that bioavailability is virtually zero. For drugs with an active metabolite, the therapeutic consequence of first-pass metabolism depends on the contributions of the drug and the metabolite to the desired and undesired effects. | 當一個藥物能迅速溶解并容易穿透細胞膜時，吸收趨向于完全。但口服給藥時的吸收并不總是完全的。藥物在到達腔靜脈之前必先沿著胃腸道下行并通過腸壁和肝臟這些通常的藥物代謝部位；這樣,藥物在進入體循環(huán)可供測量之前就可能被代謝（首過代謝）。許多藥物由于首過代謝強而生物利用度低。這些組織對這些藥物（如異丙腎上腺素、去甲腎上腺素、睪酮）的代謝很完全以至它們的生物利用度實際上為零。對于那些生成活性代謝物的藥物來講,經(jīng)過首過代謝的治療上的重要性取決于藥物和代謝物所引起的期望的和非期望的效應(yīng). |
| Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. More factors can affect bioavailability when absorption is slow or incomplete than when it is rapid and complete, so slow or incomplete absorption often leads to variable therapeutic responses. | 低生物利用度最常見于水溶性差、吸收慢的藥物的口服劑型。與吸收慢和不完全的藥物相比，吸收迅速而完全的藥物的生物利用度影響因素更多。因此，吸收緩慢或不完全常常導致治療學效應(yīng)的不同?！?/td> |
| Insufficient time in the GI tract is a common cause of low bioavailability. Ingested drug is exposed to the entire GI tract for no more than 1 to 2 days and to the small intestine for only 2 to 4 h. If the drug does not dissolve readily or cannot penetrate the epithelial membrane （eg, if it is highly ionized and polar）, time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, activity, genetic phenotype, stress, disease （eg, achlorhydria, malabsorption syndromes）, or previous GI surgery can affect drug bioavailability. | 藥物在胃腸道內(nèi)停留時間不充分是低生物利用度的常見原因。所攝入藥物在整個消化道的停留時間不超過1~2天，在小腸的停留時間也只有2~4小時，如果藥物溶解不迅速或不能穿透上皮細胞膜（如藥物高度解離和極性強），藥物在吸收部位的停留時間就可能不充分。在這種情況下，生物利用度往往變化更大，也很低。年齡、性別、活動情況、遺傳表型、應(yīng)激、疾?。ㄈ缥杆崛狈?營養(yǎng)不良綜合征）或既往胃腸手術(shù)等均能影響藥物的生物利用度?！?/td> |
| Reactions that compete with absorption can reduce bioavailability. They include complex formation （eg, between tetracycline and polyvalent metal ions）, hydrolysis by gastric acid or digestive enzymes （eg, penicillin and chloramphenicol palmitate hydrolysis）, conjugation in the gut wall （eg, sulfoconjugation of isoproterenol）, adsorption to other drugs （eg, digoxin and cholestyramine）, and metabolism by luminal microflora. | 妨礙吸收的許多反應(yīng)能降低生物利用度。這些反應(yīng)包括絡(luò)合物的形成（例如，四環(huán)素與多價金屬離子形成絡(luò)合物），被胃酸或消化酶水解（如青霉素和棕櫚酸氯霉素的水解），在腸壁進行結(jié)合反應(yīng)（如異丙腎上腺素的硫酸結(jié)合反應(yīng)），吸附于其他藥物（如地高辛和消膽胺）以及被腸道菌叢代謝?！?/td> |
| Assessment of Bioavailability | 生物利用度的評估 |
| Assessment of bioavailability from plasma concentration-time data usually involves determining the maximum （peak） plasma drug concentration, the time at which maximum plasma drug concentration occurs （peak time）, and the area under the plasma concentration-time curve. The plasma drug concentration increases with the extent of absorption; the peak is reached when the drug elimination rate equals absorption rate. Bioavailability determinations based on the peak plasma concentration can be misleading, because drug elimination begins as soon as the drug enters the bloodstream. The most widely used general index of absorption rate is peak time; the slower the absorption, the later the peak time. However, peak time is often not a good statistical measure because it is a discrete value that depends on frequency of blood sampling and, in the case of relatively flat concentrations near the peak, on assay reproducibility. | 按血漿濃度－時間數(shù)據(jù)評估生物利用度通常用到三個參數(shù)：最大（峰）血漿藥物濃度（血藥濃度），達到最大血漿藥物濃度的時間（達峰時間）和血漿濃度－時間曲線下面積。血藥濃度隨著吸收分量的增加而增加；在藥物消除率與吸收率相等時就達到血濃度高峰。單靠峰時血漿濃度來確定生物利用度會導致誤解，因為藥物一進入血流就會開始藥物消除。使用最廣泛的吸收速率指標是藥峰時間；吸收越慢，藥峰時間越滯后。然而，藥峰時間也不經(jīng)常是一個好的統(tǒng)計指標，因為它是一個離散值，其大小依賴于采血樣的頻率以及――在接近高峰血藥濃度相對平坦的情況下――測定的重現(xiàn)性?！?/td> |
| AUC is the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation. For an accurate measurement, blood must be sampled frequently over a long enough time to observe virtually complete drug elimination. Drug products may be considered bioequivalent in extent and rate of absorption if their plasma-level curves are essentially superimposable. Drug products that have similar AUCs but differently shaped plasma-level curves are equivalent in extent but differ in their absorption rate-time profiles. | AUC是最可靠的生物利用度指標。它直接與到達體循環(huán)的原形總藥量成正比。為了測得精確的AUC，必須采多次血樣，一直到藥物在體內(nèi)實際上完全消除為止。不同的藥物制品，當其血漿濃度曲線基本上重疊時，就可認為它們在吸收分量和速率方面是生物等效的。一些AUC相同而血漿濃度曲線形狀不同的藥物，具有相同的吸收分量和不同的吸收速率－時間?！?/td> |
| Single vs. multiple doses: Bioavailability may be assessed after single or repetitive （multiple） dosing. More information about rate of absorption is available after a single dose than after multiple dosing. However, multiple dosing more closely represents the usual clinical situation, and plasma concentrations are usually higher than those after a single dose, facilitating data analysis. After multiple dosing at a fixed-dosing interval for four or five elimination half-lives, the blood drug concentration should be at steady state （the amount absorbed equals the amount eliminated within each dosing interval）. The extent of absorption can then be analyzed by measuring the AUC during a dosing interval. Measuring the AUC over 24 h is probably preferable because of circadian variations in physiologic functions and because of possible variations in dosing intervals and absorption rates during a day. | 單次和多次給藥 可采用單次或多次給藥法評估生物利用度。單次給藥所獲得的吸收速率信息要比多次給藥獲得的多，但多次給藥反映臨床狀況更確切，所獲得的血漿濃度也高于單次給藥，更易于數(shù)據(jù)分析。以固定間隔時間多次給藥，經(jīng)過4~5個消除半衰期，血藥濃度就應(yīng)接近穩(wěn)態(tài)（即在每一固定間隔時間內(nèi)，吸收的藥量等于消除的藥量）。吸收分量即可通過測定一個給藥間隔時間的AUC測得。由于生理功能的晝夜變化，由于一天內(nèi)給藥間隔和吸收速率也可能發(fā)生變化，因此，24小時測一次AUC可能是最好的?！?/td> |
| For drugs excreted primarily unchanged in urine, bioavailability can be estimated by measuring the total amount of drug excreted after a single dose. Ideally, urine is collected over a period of 7 to 10 elimination half-lives for complete urinary recovery of the absorbed drug. Bioavailability may also be assessed after multiple dosing by measuring unchanged drug recovered from urine over 24 h under steady-state conditions. | 對那些以原形經(jīng)尿排出為主的藥物而言，其生物利用度可以通過測量單次用藥后尿藥總量來評估。較理想的做法是，收集尿液時間長達7~10個消除半衰期，使所吸收的藥物全部出現(xiàn)在尿中。生物利用度也可在多次給藥達到穩(wěn)態(tài)的條件下，通過測量24小時尿中出現(xiàn)的原型藥來評估?！?/td> |
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