生物技术药物的药代动力学特点及检测.ppt
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1、生物技术药物的药代动力学特点及检测,广州蓝韵医药研究有限公司专注于中药新药临床前研究,保健品研发,Cumulative Revenues of Selected Biotechnology Companies(Amgen,Genentech,Chiron,Genzyme and Biogen),Selected Blockbuster Protein Pharmaceuticals,生物技术药物,重组蛋白多肽类单克隆抗体及其片断寡核苷酸疫苗制剂基因治疗药物(核酸制剂)干细胞药物?,蛋白肽类药物药代动力学,吸收分布代谢与排泄,蛋白肽类药物吸收,小分子多肽:被动吸收大分子多肽:水溶性:细胞间隙脂溶
2、性:膜脂扩散胞饮淋巴系统吸收:po干扰素;高度脂溶性?影响蛋白肽类药物吸收因素药物稳定性;细胞渗透性:MW1000,鼻粘膜肠粘膜,Correlation between MW and the cumulative recovery of sc rINF alpha-2a,cytochrome c,inulin and 5-fluoro-2-deoxyuridine(FUDR)in the efferent lymph in sheep,蛋白肽类药物吸收,非肠道给药(Parenteral Route):IVMSCIP鼻腔肺直肠回肠阴道颊口服鼻腔给药(Intranasal administrati
3、on);Inhale administration;口服给药(Oral administration)Peroral administration经皮给药(Transdermal administration);其他给药途径:结肠、回肠、子宫、阴道、颊、眼睛等。,IM 和SC给药生物利用度,Pharmacokinetics of IM ADI-SS PEG 20,000 mw in humans with hepatocellular carcinoma,Intranasal administration,易给药;鼻粘膜上皮细胞有大量的微绒毛和广泛分布的血管淋巴管;无肝首过效应;伪首过效应(P
4、seudofirstpass effect);多肽、蛋白酶(主要是氨肽酶);calcitonin,oxytoxin,LH-RH,growth hormone,interferone,vaccines;分子量up to 2 KDa:pharmacologically acitive;血脑屏障:IGF-1。,Inhalation administration,Ease of administrationlarge surface area(75 m2)High vascularityBypass of first-pass metabolism Insulin for Type II diabet
5、esDornase-alpha for cyctic fibrosis,Proteases in the lungLocal effectsEffect of molecular weight?,Plasma bioavailability of therapeutic peptides versus MW after pulmonary administration,Oral administration,Generally not therapeutically active;Factors for lack of systemic bioavailability:high gastroi
6、ntestinal enzyme activitygastrointestinal mucosa as an absorption barrier;cytochrome P450 3A and p-glycoprotein activityAvailable oral forms:cyclosporine(30%)and desmopressin(0.16%);Absorption enhancers;encapsulation in microparticles or nanoparticles.,蛋白肽类药物的分布,分布容积小:0.04-0.2 L/kg vs.1-20 L/kg(小分子)
7、;分子量大;水溶性大;蛋白结合率高?中央室(Vc):3-8 L=plasma volume和平衡室(Vss):14-20 L2x中央室;蛋白结合:reduce clearance;Site-specific and target-oriented receptor mediated uptake,蛋白肽类药物分布:血脑屏障,血脑屏障:缺乏特异转运系统;存在蛋白分解酶;外排作用泵提高血脑屏障对蛋白多肽类药物摄取的方法:脂质体鼻腔给药;脊髓管灌注或泵连续输注。,Ziconotide cerebrospinal CSF concentration as a function of time,CSF
8、Ziconotide Pharmacokinetic Results by Dose Group,小分子药物代谢,Drug biotransformation is divided into two types of reactions:phase I(hydrolysis,oxidation,and reduction)phase II reactions:conjugation(uridine diphosphoglucuronosyl transferase(UGT),N-acetyl transferase(NAT),glutathione S-transferase(GST),and
9、 sulfotransferase(ST).,小分子药物代谢,蛋白肽类药物代谢与排泄(消除:elimination),蛋白水解酶(溶酶体、蛋白酶、组织蛋白酶、氨肽酶、二肽酶):throughout bodyProteosesPeptisases受体介导清除(receptor-mediated endocytosis):t-PAliverlow density lipoprotein receptor-mannose-asialogglycoprotein receptor;insulin蛋白水解酶稳定:环孢菌素P450?,蛋白肽类药物代谢与排泄,肾脏肾小球:30 Kd,eg.,IFN,IL-2
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- 生物技术 药物 动力学 特点 检测
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