Prodrug is an effective way to improve the oral absorption of the drugs which belong to Biopharmaceuticals Classification System (BCS) class III and IV. This review addresses the progress of the oral prodrugs in recent years, mainly including classical prodrug design and targeted prodrug design. Classical prodrug design is focused on modification of oil-water partition coefficient or decrease the metabolism of parent drugs. Targeted prodrug design is actively concerned with the physiological characteristics of the gastrointestinal tract to target tissues, enzymes and influx transporters. Intestinal influx transporter, the peptide transporter-targeted prodrug design is a growing field of the research of oral prodrugs recently. Challenges of prodrug strategy, design and investigation in vivo are also discussed.
Administration, Oral ; Animals ; Biological Transport ; Drug Delivery Systems ; Drug Design ; Humans ; Intestinal Absorption ; Prodrugs ; administration & dosage ; pharmacokinetics ; Solubility

Targeted drug delivery can significantly increase the concentration of the drug in treatment site, and decrease the dosage of drugs, cost of treatment and the drug's adverse effects on the body. So targeted drug delivery is the hotspot of recent studies. This paper reviews the development of targeted drug delivery research in recent years, including three areas: passive targeting, active targeting, and physical and chemical targeting.
Animals ; Antibodies ; metabolism ; Drug Carriers ; Drug Delivery Systems ; methods ; trends ; Emulsions ; Humans ; Liposomes ; Magnetics ; Microspheres ; Nanoparticles ; Pharmaceutical Preparations ; administration & dosage ; Photosensitizing Agents ; pharmacology ; Prodrugs ; Receptors, Cell Surface ; metabolism

The primary objective of this study was to compare thepharmacokinetics of a new anti-human immunodeficiencyvirus agent 1-(2-amino-pyridin-4-ylmethyl)-6-(3,5-dimethyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (VP-0502)with its amino acid prodrug alanine amide of VP-0502(VP-0502AL), following intravenous and oral administrationsto rats. The plasma concentrations of both analytes wereanalyzed via high-performance liquid chromatographycoupled with photodiode-array detection (HPLC-DAD).When VP-0502 was intravenously administered at 20mg/kg, the analyte appeared in low levels with an AUC of 0.3microg.h/ml, and C0 of 0.2microg/ml in plasma. However, boththe prodrug VP-0502AL and its metabolite VP-0502 appearedat comparatively higher levels following intravenousinjection of VP-0502AL at the same dose. VP-0502AL'spharmacokinetic parameters were Vd: 4.6 l/kg; AUC:3microg.h/ml; t1/2: 0.5h; C0: 6microg/ml; CLtot: 7l/h/kg; andMRT: 0.6h. Following oral administration of VP-0502(100mg/kg), it was not detectable in plasma (<50ng/ml),while after the oral administration of VP-0502AL, VP-0502 was quantitatively detected as an active metabolite forthe first 7h, with a maximum plasma concentration(Cmax) of 0.8microg/ml, and an area under the concentration-time curve (AUC) of 2microg.h/ml. The oral pharmacokineticparameters of VP-0502AL were calculated to be: maximumconcentration time (tmax) 2.7h; Cmax 0.2microg/ml; eliminationhalf-life (t1/2): 0.8h; and AUC 0.5microg.h/ml. Overall thefindings indicate that VP-0502AL has a favorable pharmaco-kinetic profile as a prodrug with rapid transformationinto the active metabolite, and that the attachment of theamino acid alanine to VP-0502 is an effective approach toimprove its oral bioavailability. VP-0502AL is predictedto become a new highly bioavailable anti-AIDS drugcandidate and/or lead compound.
Administration, Oral ; Alanine/*analogs & derivatives/pharmacokinetics ; Aminopyridines/*pharmacokinetics ; Animals ; Anti-HIV Agents/administration & dosage/blood/*pharmacokinetics ; Area Under Curve ; Biological Availability ; Half-Life ; Injections, Intravenous ; Male ; Prodrugs/administration & dosage/*pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Uracil/*analogs & derivatives/pharmacokinetics

AIMEnteric microspheres were prepared to prevent the interaction of drug with gastric acid and to improve its bioavailability.

METHODSThe enteric microspheres with a matrix structure were successfully produced using a spherical crystallization technique. Hydroxypropyl methylcellulose phthalate (HP-55), an enteric material, was coprecipitated with the drug by salting-out effect during the preparation process. A mixture of water and ethanol was chosen as a good solvent and dichloromethane was used as a bridging agent while 0.1 mol x L(-1) sodium chloride solution was selected as a poor solvent.

RESULTSIt is the first time to prepare microspheres by making the water-soluble drug and water-insoluble excipient coprecipitated. In vivo test demonstrated that the drug absorption from the enteric oleanolic acid dihemiphthalate sodium (OADHPS) microspheres was significantly prolonged compared to that with OADHPS powder after a lag-time. Furthermore, the drug bioavailability was 181.6% greater than that with the OADHPS powder.

CONCLUSIONThe microspheres of water soluble drug could be prepared by using water phase replacing organic phase as poor solvent which decrease the quantity of organic solvent and benefit the environment prevention.

Animals ; Area Under Curve ; Biological Availability ; Delayed-Action Preparations ; Dogs ; Drug Carriers ; Drug Compounding ; methods ; Male ; Methylcellulose ; analogs & derivatives ; chemistry ; Microspheres ; Oleanolic Acid ; administration & dosage ; pharmacokinetics ; Particle Size ; Prodrugs ; administration & dosage ; pharmacokinetics ; Salts ; Solubility

PURPOSE: The aim of the study was to compare the efficacy of parecoxib for postoperative analgesia after endoscopic turbinate and sinus surgery with the prodrug of acetaminophen, proparacetamol. MATERIALS AND METHODS: Fifty American Society of Anesthesiology (ASA) physical status I-II patients, receiving functional endoscopic sinus surgery (FESS) and endoscopic turbinectomy, were investigated in a prospective, randomized, double-blind manner. After local infiltration with 1% mepivacaine, patients were randomly allocated to receive intravenous (IV) administration of either 40mg of parecoxib (n=25) or 2g of proparacetamol (n=25) 15 min before discontinuation of total IV anaesthesia with propofol and remifentanil. A blinded observer recorded the incidence and severity of pain at admission to the post anaesthesia care unit (PACU) at 10, 20, and 30 min after PACU admission, and every 1 h thereafter for the first 6 postoperative h. RESULTS: The area under the curve of VAS (AUC(VAS)) calculated during the study period was 669 (28-1901) cm·min in the proparacetamol group and 635 (26-1413) cm·min in the parecoxib group (p=0.34). Rescue morphine analgesia was required by 14 patients (56%) in the proparacetamol group and 12 patients (48%) in the parecoxib (p> or=0.05), while mean morphine consumption was 5-3.5mg and 5-2.0mg in the proparacetamol groups and parecoxib, respectively (p> or=0.05). No differences in the incidence of side effects were recorded between the 2 groups. Patient satisfaction was similarly high in both groups, and all patients were uneventfully discharged 24h after surgery. CONCLUSION: In patients undergoing endoscopic nasal surgery, prior infiltration with local anaesthetics, parecoxib administered before discontinuing general anaesthetic, is not superior to proparacetamol in treating early postoperative pain.
Acetaminophen/administration & dosage/analogs & derivatives/*therapeutic use ; Adult ; Analgesics, Non-Narcotic/administration & dosage/therapeutic use ; Cyclooxygenase Inhibitors/administration & dosage/therapeutic use ; Double-Blind Method ; Endoscopy/methods ; Female ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Isoxazoles/administration & dosage/*therapeutic use ; Male ; Middle Aged ; Nasal Polyps/surgery ; Pain, Postoperative/*drug therapy ; Prodrugs/administration & dosage/*therapeutic use ; Prospective Studies ; Sinusitis/surgery ; Treatment Outcome

OBJECTIVETo develop a colon-specific prodrug of Indomethacin microbially triggered, carry out in vitro/in vivo evaluation of drug release, and appraise its inhibitory effect on liver metastasis from colon cancer.

METHODSIndomethacin prodrugs were synthesized and characterized by FTIR and NMR, and dissolution test simulating gastrointestinal tract was employed to screen the colon-specific prodrug. Then, the pharmacokinetic profile of portal vein and peripheral blood in Sprague-Dawley rats was studied. Lastly, the inhibitory effect on liver metastasis from colon cancer in nude mice was observed.

RESULTSThe chemical structure characterized by FTIR and NMR demonstrated that six kinds of indomethacin-block-amylose with different drug loading (IDM-AM-1-6) were synthesized, among which IDM-AM-3 was degraded 1.3%, 9.3% and 95.3%, respectively, in simulated gastric fluid for 4 h, small intestine for 6 h, and colon for 36 h. The pharmacokinetic test of IDM-AM-3 showed that absorption was delayed significantly (P < 0.01), peak time [(11.35 + or - 2.45) h], elimination half-life [(16.74 + or - 4.04) h] and mean residence time [(22.27 + or - 0.52) h] were significantly prolonged (P < 0.01), as well as peak serum concentrations [(9.69 + or - 2.40) mg/L] and AUC(0-t) [(236.7 + or - 13.1) mg x L(-1) x h] were decreased markedly (P < 0.01) as compared with those of IDM regarding to portal vein. Additionally, its AUC(0-t) in peripheral blood was remarkably lower than that in Portal vein (P < 0.01). The tumor suppression observation showed that it could remarkably reduce the number of liver metastases in contrast to IDM (P < 0.05).

CONCLUSIONColon-specific IDM-AM-3 possesses advantage of sustained release in portal vein providing some experimental basis for colon-specific delivery system applied to sustained release in the portal vein.

Amylose ; administration & dosage ; chemical synthesis ; pharmacokinetics ; therapeutic use ; Animals ; Colon ; metabolism ; Colonic Neoplasms ; pathology ; Delayed-Action Preparations ; Drug Delivery Systems ; HT29 Cells ; Humans ; Indomethacin ; administration & dosage ; chemical synthesis ; pharmacokinetics ; therapeutic use ; Liver Neoplasms ; prevention & control ; secondary ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Prodrugs ; administration & dosage ; chemical synthesis ; pharmacokinetics ; therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the in vitro, in situ and in vivo killing effects to CNE-2 cells of human nasopharyngeal carcinoma (NPC) by FCU/5-FC system combined with gamma irradiation for predicting the treatment effect on NPC.

METHODSPlasmid pcDNA3.1(-)CMVe.Egr-1. FCU was introduced into CNE-2 cells by electroporation. The transfected cells were selected by G418 (600 microg/ml) for 14 days to yield cells expressing FCU stably. The FCU protein in transfected CNE-2 cells was tested by Western blotting. In vitro response of FCU-expressing CNE-2 cells to 5-FC or gamma irradiation, alone or in combination was detected by MTT assay. Furthermore, A NPC model was employed by inoculating CNE-2 cells in the right flank of nude mice for in situ gene therapy, and after 12 days of inoculation, those rats were randomized to seven groups, then the suppression of NPC growth in model was observed after giving different treatments. Finally, FCU-expressing CNE-2 cells were inoculating in the right flank of nude mice to generate NPC xenografts for in vivo gene therapy, and after 5-day of implantation, those rats were randomized to seven groups, then the delaying of tumour growth was observed in xenografts treated with different conditions.

RESULTSA anticipated relative molecular quality 42,000 protein was obtained from total protein of FCU-expressing CNE-2 cells. The growth of FCU-positive CNE-2 cells were inhibited by 5-FC or gamma irradiation, alone or in combination, but cells treated with both 5-FC and gamma irradiation resulted in enhanced cell killing when compared with cells treated with gamma irradiation or 5-FC alone. In vitro study showed that the relative survival rates of FCU-expressing CNE-2 cells treated with gamma irradiation were 15.85% - 97.88%, while that of gamma irradiation + 5-FC (100 microg/ml) group were 6.58% - 50.00%, and there was a significant difference (P < 0.01). The MTT results also demonstrated that the relative survival rate has a striking different (P < 0.01) between 5-FC group (12.11% - 99.51%) and 5-FC + gamma irradiation (1.0 Gy) group (2.37% - 35.87%). Not only in situ but also in vivo, potent growth inhibition on the explanted NPC tumours was observed in mice treated with 5-FC or gamma irradiation, alone or in combination, among which interference of both 5-FC and gamma irradiation leaded to most distinct suppression of tumour growth. Tumour volumes in groups interfered by 5-FC and or gamma irradiation were extinctly different with the control group and PBS treatment group (P < 0.05).

CONCLUSIONCNE-2 cells or nasopharyngeal carcinoma venograph could be killed by FCU/5-FC suicide gene prodrug system or gamma irradiation, and there is a synergistic therapeutic effect on NPC between FCU/5-FC and gamma irradiation.

Animals ; Antimetabolites, Antineoplastic ; administration & dosage ; therapeutic use ; Cell Line, Tumor ; Combined Modality Therapy ; Fluorouracil ; administration & dosage ; therapeutic use ; Genes, Transgenic, Suicide ; genetics ; Genetic Therapy ; methods ; Humans ; Mice ; Mice, Nude ; Nasopharyngeal Neoplasms ; pathology ; therapy ; Prodrugs ; administration & dosage ; therapeutic use ; Radiotherapy ; methods ; Time Factors ; Transfection ; Xenograft Model Antitumor Assays ; methods