512 Chapter 8 Prodrugs and Drug Delivery Systems Virus-directed enzyme prodrug therapy (VDEPT)is another gene therapy strategy that usesviral vto deliver a gene that eneodesa prodrug-activating enzyme Despite extensive use of retroviral and adenoviral vectors to deliver prodrug-activating enzyme genes both vectors have some disadvantages.The principal disadvantage of a retroviral vector is that recombnt reroiruses only target dividing cells but most human tumor cels divide slowly.Even ina rpidly growing tumor nodule,only 6-20%of the cells are in a proliferating state.Therefore,the majority of the tumor would not be sensitive to killing by retroviral VDEPT.However.this drawback could be beneficial in some cases,such as for brain tumors. because in the brain only the tumor cells would be proliferating.This would allow for a high tumor:normal transfection differential for retroviral delivery.Although most viral vectors are engineered to be replication deficient,there is a slight risk of reversion to the wild-type virus (yikes!).Furthermore,retrovirus vectors are inserted into the host-cell DNA.which may cause mutagenesis of the host's genome(double yikes!).1461 GDEPTand VDEPT have an advantage over ADEPT in that many enzymes need cofactors that are present only inside the cells.Therefore,enzymes delivered by ADEPT may need to gain access to the inside of tumor cells before they can optimally activate prodrugs.This is a problem because of the poor cell penetration of antibody-enzyme conjugates.In GDEPT gene-encoding enzymes can be specifically delivered to target tissues,which allows for the expression of the enzyme within the target cells47Problems associated with GDEPTinclude insertional mutagenesis,anti-DNA antibody formation,local infection,and tumor nodule ulceration as well as difficulties with the selective delivery and expression of the genes.4 d.Prodrugs for Stability Some prodrugs protect the drug from the first-pass effect(see Chapter 7.Section 7.1.p.406). Propranolol(8.22,R =R'=H;Inderal)is a widely used antihypertensive drug.but because of first-pass elimination,an oral dose has a much lower bioavailability than does intravenous injection.The major metabolites(see Chapter 7)are propranolol O-glucuronide (8.22.R =H.OR'=glucuronide).p-hydroxypropranolol (8.22.R =OH.R'=H)and its O-glucuronide(8.22.R =OH.OR'=glucuronide).The hemisuccinate ester of propra- nolol (8.22,R=H,R'=COCH2CH2COOH)was prepared to block glucuronide formation: following oral administration of propranolol hemisuccinate,the plasma levels of propranolol were eight times greater than when propranolol was used.501 NHCHICH边 propanolol (R=R'=H) 8.22 Naltrexone (8.23.R =H:Trexan).used in the treatment of opioid addiction,is nonaddicting and is well absorbed from the gastrointestinal tract.However,it under- goesextenivefirst-pass metabolism when given orally.Ester prodrugs.the anthranilate (823.R-CO-o-NOPh)and the acetylsalicylate (8.23.RCO-o-AcO-Ph).enhanced the bioavailability 45-and 2-fold,respectively,relative to 8.23(RH).151
Seon8.2 Mechanisms of Drug Activation 513 RO naltrexone(R=H) 8.23 e. Prodrugs for Slow and Prolonged Release The utility of slow and prolonged release of drugs is several-fold:(1)It reduces the number and frequency of doses required.(2)It eliminates nighttime administration of drugs.(3)Because the drug is taken less frequently,it minimizes patient noncompliance.(4)When a fast-release drug is taken,there is a rapid surge of the drug throughout the body.As metabolism of the drug proceeds.the concentration of the drug diminishes.A slow-release drug would eliminate these peaks and valleys of fast-release drugs,which place a strain on cells.(5)Because a constant lower concentration of the drug is being released,it reduces the possibility of toxic levels of drugs.(6)It reduces gastrointestinal side effects.A common strategy in the design of slow-release prodrugs is to make a long-chain aliphatic ester,because these esters hydrolyze slowly,and to inject them intramuscularly. Prolonged release drugs are quite important in the treatment of psychoses because these patients require medication for extended periods of time and often show high patient non- compliance rates.Haloperidol(8.24.R =H:Haldol)is a potent,orally active central nervous system depressant,sedative,and tranquilizer.However,peak plasma levels are observed between 2 and 6h after administration.The ester prodrug haloperidol decanoate (8.24.R =CO(CH2)8CH3:Haldol Decanoate)is injected intramuscularly as a solution in sesame oil,and its antipsychotic activity lasts for about I month.21 The antipsychotie fluphenazine(8.25.R-H;one trade name is Prolixin)also has a short duration of activity (6-8h).Fluphenazine enanthate(8.25,R=CO(CH2)sCH3:Prolixin Enan)and fluphenazine decanoate(8.25,R=CO(CH2)sCH3:Prolixin Dec),however,have durations of activity of about I month.53) -OR fluphenazine(R H) fluphenazine ethanate(R=CO(CH2)sCHa) haloperidol(R=H) fluphenazine decanoate(R CO(CHz)CH.) haloperidol decanoate(R=CO(CH2)sCHa) 825 Conversion of the nonsteroidal anti-inflammatory (antiarthritis)drug tolmetin sodium 824 (8.26.R-O-Na+:Tolectin)to the corresponding glycine conjugate (8.26.R=