3'-Azido-2',3'-dideoxythymidine (AZT, 1, zidovudine, RetrovirTM) is used to treat patients with human immunodeficiency virus (HIV) infection. AZT, after conversion to AZT-5'-triphosphate (AZT-TP) by cellular enzymes, inhibits HIV-reverse transcriptase (HIV-RT). The major clinical limitations of AZT are due to clinical toxicities that include bone marrow suppression, hepatic abnormalities and myopathy, absolute dependence on host cell kinase-mediated activation which leads to low activity, limited brain uptake, a short half-life of about one hour in plasma that dictates frequent administration to maintain therapeutic drug levels, low potential for metabolic activation and/or high susceptibility to catabolism, and the rapid development of resistance by HIV-1. These limitations have prompted the development of strategies for designing prodrugs of AZT. A variety of 5'-O-substituted prodrugs of AZT constitute the subject of this review. The drug-design rationale on which these approaches are based is that the ester conjugate will be converted by hydrolysis and/or enzymatic cleavage to AZT or its 5′-monophosphate (AZT-MP). Most prodrug derivatives of AZT have been prepared by derivatization of AZT at its 5'-O position to provide two prominent classes of compounds that encompass: A) 5'-O-carboxylic esters derived from 1) cyclic 5'-O-carboxylic acids such as steroidal 17b-carboxylic acids, 1-adamantanecarboxylic acid, bicyclam carboxylic acid derivatives, O-acetylsalicylic acid, and carbohydrate derivatives, 2) amino acids, 3) 1, 4-dihydro-1-methyl-3-pyridinylcarboxylic acid, 4) aliphatic fatty acid analogs such as myristic acid containing a heteroatom, or without a heteroatom such as stearic acid, and 5) long chain polyunsaturated fatty acid analogs such as retinoic acid, and B) masked phosphates such as 1) phosphodiesters that include monoalkyl or monoaryl phosphate, carbohydrate, ether lipid, ester lipid, and foscarnet derivatives, 2) a variety of phosphotriesters that include dialkylphosphotriesters, diarylphosphotriesters, glycolate and lactate phosphotriesters, phosphotriester approaches using simultaneous enzymatic and chemical hydrolysis of bis(4-acyloxybenzyl) esters, bis(S-acyl-2-thioethyl) (SATE) esters, cyclosaligenyl prodrugs, glycosyl phosphotriesters, and steroidal phosphotriesters, 3) phosphoramidate derivatives, 4) dinucleoside phosphate derivatives that possess a second anti-HIV moiety such as AZT-P-ddA, AZT-P-ddI, AZTP2AZT, AZTP2ACV), and 5) 5'-hydrogen phosphonate and 5'-methylene phosphonate derivatives of AZT. In these prodrugs, the conjugating moiety is linked to AZT via a 5'-O-ester or 5'-O-phosphate group. 5'-O-Substituted AZT prodrugs have been designed with the objectives of improving anti-HIV activity, enhancing blood-brain barrier penetration, modifying pharmacokinetic properties to increase plasma half-life and improving drug delivery with respect to site-specific targeting or drug localization. Bypassing the first phosphorylation step, regulating transport and conferring sustained release of AZT prolong its duration of action, decrease toxicity and improve patient acceptability. The properties of these prodrugs and their anti-HIV activities are now reviewed.

1997-11-01·Antimicrobial Agents and Chemotherapy2区 · 医学

Comparative metabolism of the antiviral dimer 3'-azido-3'-deoxythymidine-P-2',3'-dideoxyinosine and the monomers zidovudine and didanosine by rat, monkey, and human hepatocytes

2区 · 医学

Article

作者: Duchin, K ; Schinazi, R F ; Rahmani, R ; Xie, M Y ; Pan-Zhou, X R ; Zhou, X J ; Sommadossi, J P ; Cretton-Scott, E

AZT-P-ddI is an antiviral heterodimer composed of one molecule of 3'-azido-3'-deoxythymidine (AZT) and one molecule of 2',3'-dideoxyinosine (ddI) linked through their 5' positions by a phosphate bond. The metabolic fate of the dimer was studied with isolated rat, monkey, and human hepatocytes and was compared with that of its component monomers AZT and ddI. Upon incubation of double-labeled [14C]AZT-P-[3H]ddI in freshly isolated rat hepatocytes in suspension at a final concentration of 10 microM, the dimer was taken up intact by cells and then rapidly cleaved to AZT, AZT monophosphate, ddI, and ddI monophosphate. AZT and ddI so formed were then subject to their respective catabolisms. High-performance liquid chromatography analyses of the extracellular medium and cell extracts revealed the presence of unchanged dimer, AZT, 3'-azido-3'-deoxy-5'-beta-D-glucopyranosylthymidine (GAZT), 3'-amino-3'-deoxythymidine (AMT), ddI, and a previously unrecognized derivative of the dideoxyribose moiety of ddI, designated ddI-M. Trace extracellular but substantial intracellular levels of the glucuronide derivative of AMT (3'-amino-3'-deoxy-5'-beta-D-glucopyranosylthymidine [GAMT]) were also detected. Moreover, the extent of the formation of AMT, GAZT, and ddI-M from the dimer was markedly lower than that with AZT and ddI alone by the hepatocytes. With hepatocytes in primary culture obtained from rat, monkey, and human, large interspecies variations in the metabolism of AZT-P-ddI were observed. While GAZT and ddI-M, metabolites of AZT and ddI, respectively, as well as AZT 5'-monophosphate (MP) and ddI-MP were detected in the extracellular media of all species, AMT and GAMT were produced only by rat and monkey hepatocytes. No such metabolites were formed by human hepatocytes. The metabolic fate of the dimer by human hepatocytes was consistent with in vivo data recently obtained from human immunodeficiency virus-infected patients.

1997-03-01·The Journal of Clinical Pharmacology3区 · 医学

Phase I Dose‐Escalation Pharmacokinetics of AZT‐P‐ddI (IVX‐E‐59) in Patients with Human Immunodeficiency Virus

3区 · 医学

Article

作者: Kirk, M ; Pan-Zhou, X R ; Bernhard, S ; Duchin, K L ; Zhou, X J ; Sommadossi, J P ; Squires, K ; Agrofoglio, L

3′‐Azido‐3′‐deoxythymidilyl‐(5′,5′)‐2′,3′‐dideoxy‐5′‐inosinic acid (AZT‐P‐ddI, IVX‐E‐59, Scriptene) is a heterodimer composed of one molecule of 3′‐azido‐3′‐deoxythymidine (zidovudine or AZT) and one molecule of 2′,3′‐dideoxyinosine (didanosine or ddI) linked through their 5′ positions by a phosphate bond. AZT‐P‐ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT‐P‐ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3. Isotopic preparations of (14C)‐AZT‐P‐(3H)‐ddI were administered intravenously (50 mg and 100 mg) to eight patients; 1 month later these patients were crossed over to oral administration (100 mg and 200 mg). A second group of patients (n = 4) received only a 450‐mg oral dose of AZT‐P‐ddI. Plasma levels of unchanged AZT‐P‐ddI after intravenous infusion declined rapidly and were undetectable 0.75 hours after the end of infusion, whereas the parent compound was not detected after oral administration, indicative of a very rapid metabolism. The parent entity was enzymatically cleaved in vivo yielding the two constituent drugs AZT and ddI, which were subsequently subjected to their respective pharmacokinetic and metabolic processes. The β‐glucuronide derivative of AZT (GAZT) represented the major metabolite of AZT, but there were no detectable levels of the toxic metabolite 3′‐amino‐3′‐deoxythymidine (AMT). A major and previously unrecognized in vivo metabolite of ddI, referred as ddI‐M, was detected in plasma and urine. Analysis by high‐field proton nuclear magnetic resonance and mass spectrometry led to the identification of ddI‐M as being R(–)‐dihydro‐5‐(hydroxymethyl)‐2(3H)‐furanone. The formation of AZT and ddI metabolites was increased after oral administration of AZT‐P‐ddI compared with the intravenous infusion, with an area under the concentration—time curve (AUC) ratio of metabolite to AZT and metabolite to ddI being 7.7 and 5.7 (oral) and 3.8 and 1.1 (intravenous), respectively. The newly identified ddI‐M exhibited sustained plasma levels for extended time periods with an apparent elimination half‐life (t1/2) of approximately 10 hours after oral administration of AZT‐P‐ddI. Recovery of radioactivity associated with 3H and 14C in urine was essentially complete within 48 hours after oral and intravenous administration of AZT‐P‐ddI. The oral bioavailability of AZT (64.7–67.3%) and ddI (33.6–42.9%) and the other pharmacokinetic parameters were consistent with previous data reported with each nucleoside analog alone or in combination therapy.

100 项与 IVX-E-59(Teva Pharmaceutical Industries Ltd.) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
HIV感染	临床2期	-	Teva Pharmaceutical Industries Ltd.	-
HIV感染	临床2期	-	C.H. Boehringer Sohn AG & Co. KG	-
HIV感染	临床2期	美国	-	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


VESD study (IAS2005)	N/A	-	163	ddI-3TC-EFV	鹽積網觸淵觸壓糧艱鏇(憲夢壓網壓繭艱鹹醖夢) = 選觸壓餘糧蓋壓鑰蓋憲鹹選鬱夢淵醖觸餘蓋衊 (選餘築觸鏇糧夢醖遞範 )	-	2005-01-01
VESD study (IAS2005)	N/A	-	163	ddI-3TC-EFV	(範鹽膚艱蓋鬱構廠鏇衊) = 廠繭構鬱簾鹹築蓋簾願膚製糧膚鏇顧遞窪鬱衊 (觸齋簾築鹽鬱蓋膚製壓 ) 更多	积极	2005-01-01
EFADITE Trial (IAS2005)	N/A	-	-	QD ddI-TDF-EFV	廠膚鑰餘糧構範鑰窪獵(蓋餘積築餘獵範齋鹽繭) = 簾構壓鬱選壓積憲衊憲範製夢蓋糧窪願顧構壓 (壓簾齋獵顧構鏇壓衊淵 ) 更多	-	2005-01-01
EFADITE Trial (IAS2005)	N/A	-	-	Didanosine (Controls)	廠膚鑰餘糧構範鑰窪獵(蓋餘積築餘獵範齋鹽繭) = 鹽網鏇選壓膚艱蓋觸製範製夢蓋糧窪願顧構壓 (壓簾齋獵顧構鏇壓衊淵 ) 更多	-	2005-01-01