【正文】 HON H 2 O HO+ + +O HOOC O 2? XP13512是加巴噴丁的轉(zhuǎn)運(yùn)前體藥（ Transported Prodrug），與 P450或 Pgp不發(fā)生相互作用，是兩種在全腸道表達(dá)的轉(zhuǎn)運(yùn)體MCT1和 SMVT的底物 ? 在腸，肝和血被非特異性酯酶裂解生成加巴噴丁。在寬劑量范圍內(nèi)與加巴噴丁生物利用度（ ≥70%）成正比。與加巴噴丁比較，猴子口服后，血漿中加巴噴丁 Cmax增加 5倍， AUC增加 3倍 加巴噴丁 XP13512 Stomach Small Intestine Colon 2 to 4 hours 1 to 6 hours 8 to 18 hours Limited Capacity Absorption Window ? Saturable uptake – exposure not proportional to dose ? Variable capacity/transit times intersubject variability in PK ? No colonic absorption SR formulation not possible Gabapentin Has a Limited GI Absorption Window Transit Time in Humans 氨基酸轉(zhuǎn)運(yùn)體底物 Overing a Limited Absorption Window Stomach Small Intestine Colon 2 to 4 hours 1 to 6 hours 8 to 18 hours High Capacity Transporter ? Increased bioavailability ? Greater dose proportionality ? Lower interpatient variability ? Reduced dosing frequency (sustained release) Modify the drug for recognition by high capacity transporters located throughout the intestine: MCT1和 SMVT的底物 XP13512 (IR) vs. Neurontin: Concentrations of Gabapentin in Blood Effect of Dose on Concs. of Gabapentin in Blood After Oral Administr. of Neurontin or XP13512 to Healthy Adults Conce nt ra t ions of G aba pen t in in B lood A f t er O ra lA dm inist ra t ion of Neur ontin in S t udy X P 006Time (h r)0 6 12 18 24 30 36Concentration (ug/mL)024681012141618Neur ontin 200 mgNeur ontin 400 mgNeur ontin 800 mgNeur ontin 120 0 mgNeur ontin 140 0 mgConce nt ra t ions of G aba pen t in in B lood A f t er O ra lA dm inist ra t ion of X P 135 12 in S t udy X P 006Time (h r)0 6 12 18 24 30 36Concentration (ug/mL)024681012141618X P 135 12 350 mgX P 135 12 700 mgX P 135 12 1400 mg X P 135 12 2100 mgX P 135 12 2800 mgAll AEs reported for XP13512 were mild and similar to those reported for Neurontin Dose P ro por t iona lit y of G aba pen t in in B lood A f t erO ra l A dm inist ra t ion of X P 135 12 or Neur ontin in S t udy X P 006Dose (mg equ iv alen t s of G aba pen t in/ kg)0 200 400 600 800 1000 1200 1400 1600Gabapentin AUC (ug.hr/mL)020406080100120140160180X P 135 12 Neur ontin XP13512: Dose Proportionality of AUC Effect of Dose on AUC of Gabapentin in Blood After Oral Administration of XP13512 or Neurontin XP13512 produced doseproportional exposure Neurontin exposure showed saturation R2 = B ioav aila bilit y of G aba pen t in A f t er O ra l A dm inist ra t ionof X P 135 12 or Neur ontin in S t udy X P 006Dose (mg equ iv alen t s of G aba pen t in)0 200 400 600 800 1000 1200 1400 1600Bioavailability (%)0102030405060708090100X P 135 12 Neur ontin XP13512: High Bioavailability as Gabapentin Effect of Dose on Bioavailability as Gabapentin After Oral Administration of XP13512 or Neurontin174。 to Healthy Volunteers Neurontin absorption was saturated No saturation of XP13512 absorption or conversion to gabapentin Conce nt ra t ions of G aba pen t in and P ro dr ug in B lood A f t erO ra l A dm inist ra t ion of 280 0 mg X P 135 12 in S t udy X P 006Time (h r)0 6 12 18 24 30 36Concentration (ug/mL)024681012141618G aba pen t inP ro dr ugXP13512: Very Low Exposure to Prodrug Concs of Gabapentin and Intact XP13512 in Blood After Oral Administ of XP13512 to Healthy Volunteers at 2800 mg Gabapentin Cmax was 50fold higher than prodrug Cmax Gabapentin AUC was 280fold higher than prodrug AUC 3. 基于代謝物的新藥發(fā)現(xiàn)和藥物設(shè)計(jì) ? 研究藥物在體內(nèi)外的 代謝物 ? 設(shè)計(jì) 生物轉(zhuǎn)化激活的前體藥物 ? 發(fā)現(xiàn) 一些活性代謝物比母體藥物更安全有效或再經(jīng)過(guò) 結(jié)構(gòu)修飾 發(fā)現(xiàn)新藥 ? 新藥發(fā)現(xiàn)和藥物設(shè)計(jì)的一種重要來(lái)源 OCH 3 CN HC C H 3OH 2H 3 C CHO+H O N HC C H 3O非 那 西 丁 撲 熱 息 痛C Y P 1 A 2Phenacetin, 1887 (nephrotoxic, methemoglobinemia) Recognized as active metabolite of phenacetin in 1948。 popular in US since 1955 磺胺 還原 CYP3A4 Terfenadine (Seldane) Fexofenadine (Allegra) NHOOH NHOCO 2 HOHCYP3A4,2C19 Diazepam Oxazepam 4. 藥物代謝性質(zhì)用于制劑設(shè)計(jì) ? 抗哮喘藥異丙腎上腺素 ? 在腸道和肝中代謝而迅速失活，口服給藥方式無(wú)法使其有效到達(dá)作用部位肺組織 ? 采用噴霧劑吸入給藥，這樣可繞過(guò)使藥物失活的代謝途徑，以足夠產(chǎn)生藥理活性的濃度到達(dá)肺組織 硫酸化 葡萄糖醛酸化 氧化 ? 腸道代謝在口服給藥中也可作為有利的一面加以應(yīng)用 ? 琥珀酰磺胺噻唑 （ succinylsulfathiazole） 的腸吸收較差，但是易被腸道酶水解生成有活性的磺胺噻唑（ sulfathiazole） ? 這種局部水解作用可保證腸道中有效的抗菌濃度，有利于治療腸道感染 酰胺酶 ?臨床前藥物代謝動(dòng)力學(xué)技術(shù)平臺(tái) 2022ZX09304003 ? 中國(guó)人個(gè)體化用藥相關(guān)重要生物標(biāo)志物及其新型檢測(cè)試劑盒研發(fā)關(guān)鍵技術(shù) (參加 ) 2022ZX09506001004 致謝： 國(guó)家重大科技專項(xiàng)“重大新藥創(chuàng)制” 創(chuàng)新藥物研究開發(fā)技術(shù)平臺(tái)建設(shè) Spring Summer Autumn Winter West lake, Hangzhou 浙江大學(xué)紫金港校區(qū) ?UGTs的誘導(dǎo)劑 ? β萘黃酮 , 3MC,TCDD (UGT1A6/7) ? 苯巴比妥 ,苯妥英 (UGT1A1/9,2B7) ? 地塞米松 (大部分 UGT1A 和 UGT2B) ? rifampicin (UGT1A)