【Fexofenadine】評論

Cyclosporine and tacrolimus是calcineurin inhibitors，抑制T細胞內的IL-2跟其他細胞激素。從小腸吸收為主並在給藥後1-8小時達到血中濃度高峰。是親脂性藥物，分佈體積大，且Tacrolimus的蛋白質結合率高達99%。兩者主要藉由CYP3A系列代謝，並藉由膽道排泄。-Calcineurin inhibitor的機轉：Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibitors have been mainstays of immunosuppression in solid organ transplantation for over three decades.-Calcineurin inhibitor的ADME：Absorption — Oral cyclosporine and tacrolimus are only partially absorbed with large inter- and intra-individual variability. Cyclosporine and tacrolimus are absorbed in the small intestine, and peak blood concentrations occur after one to eight hours. The oral bioavailability is limited for both drugs (roughly 20 percent for tacrolimus) as a result of poor absorption, partial metabolism by enzymes in the bowel mucosa, and first-pass hepatic metabolism [39,40]. In general, modified formulations of cyclosporine lead to higher area under the time concentration curve (AUC) than the nonmodified preparations.In healthy volunteers, the oral bioavailability of extended-release tacrolimus tablets was approximately 50 percent higher as compared with tacrolimus immediate-release at steady state [37]. Both extended-release tacrolimus products exhibit chronopharmacokinetic effects; evening administration, compared with morning dosing, results in a 15 percent lower AUC for extended-release tacrolimus tablets and a 35 percent lower AUC for extended-release tacrolimus capsules [13,37]. Thus, both products should be taken consistently every morning.Pharmacokinetic trials comparing extended-release tacrolimus formulations with immediate-release tacrolimus have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration with extended-release formulations. However, extended-release tacrolimus tablets have an AUC0-24 (area under the time concentration curve from 0 to 24 hours) that is comparable with that of immediate-release tacrolimus; extended-release tacrolimus capsules have an AUC0-24 that is higher than that of immediate-release tacrolimus [13,37].The absorption and metabolism of calcineurin inhibitors may vary with race and ethnicity. As an example, the mean tacrolimus exposure after a single 5 mg oral dose in healthy Hispanic and African-American individuals was 18 and 39 percent less, respectively, than in White individuals [41]. Similar results have been seen with the extended-release products [13,37]. Such variation may be related to differences in the frequency of polymorphisms in the CYP3A5 gene among African-American, Hispanic, and White transplant recipients [42-44].Distribution — Cyclosporine and tacrolimus are lipophilic and undergo extensive body distribution. In the blood, most of the absorbed amount of each drug is taken up by erythrocytes. In the plasma, cyclosporine binds mainly to lipoproteins, whereas tacrolimus binds to proteins, primarily albumin and alpha-1-acid glycoprotein. The plasma protein binding of tacrolimus is approximately 99 percent and is independent of concentration over a range of 5 to 50 ng/mL.The highest tissue cyclosporine concentration is achieved in the thymus, spleen, lymph nodes, bone marrow, liver, pancreas, kidney, adrenal glands, lung, and skin. Tacrolimus accumulates mainly in the lung, spleen, heart, kidney, and pancreas.Metabolism — Cyclosporine and tacrolimus are extensively metabolized by cytochrome P-450 CYP3A enzymes in the liver. There is also some metabolism in the gut mucosa. The most active cyclosporine metabolites have only 10 to 20 percent of the drug's immunosuppressive activity. By comparison, one of the metabolites of tacrolimus possesses equal immunosuppressive potency to the parent drug.Elimination — Cyclosporine and tacrolimus are excreted in the bile. The elimination half-life can vary significantly among patients, especially with cyclosporine nonmodified, but is approximately 19 hours for cyclosporine modified and 12 hours for immediate-release tacrolimus. The elimination half-life of extended-release tacrolimus tablets after oral administration of 2 mg once daily for 10 days was 31±8 hours in healthy subjects [37]. The elimination half-life of extended-release tacrolimus capsules after oral administration of 4 mg capsules daily for 10 days was 38±3 hours in healthy subjects [13]. Cyclosporine metabolism is age dependent, with a 1.5- to 2.5-fold increase in half-life in adults compared with children. Liver dysfunction prolongs the half-life of both cyclosporine and tacrolimus [49,50].REF: UpToDate: Pharmacology of cyclosporine and tacrolimus

【666】評論

Tacrolimus1. 結合FKBP抑制Calcineurin，抑制T cell活化2. 用途: 併用其他免疫抑制劑預防器官移植排斥,     Off label: Crohn's disease, Graft-versus-host disease (prevention/treatment), 難治型類風濕關節炎, 重症肌無力3. 副作用: 增加移植後糖尿病, 高血鉀 (劑量相關), 增加移植後高血壓, 因抑制免疫而增加感染可能, 增加移植病人惡性淋巴瘤發生, 腎毒性, 神經毒性 (劑量相關)-震顫, 頭痛4. 代謝: CYP3A4,  P-glycoprotein/ABCB1，影響CYP3A4的藥都注意一下   (基本上是3A4啦, 但Control F搜尋uptodate也有3A5...不過要猜也猜和3A4最像的)5. 需監測全血濃度: 5-15ng/ml(ug/L)6. 99%結合albumin和alpha-1 acid glycoprotein，93%由糞便排出    肝不好要調劑量喔 (Child-Pugh class C降低起始劑量)資料來源: 自己翻譯uptodate