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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacokinetically potentiative drug combinations."]
["Potentiative effect has been determined by established methods and its molecular mechanism has been revealed."]
[]
["Biochemical class of potentiative effect ","Drug A (therapeutic or toxic effects and mechanism of actions)","Drug B (mechanism of action related to potentiative effect)","Reported potentiative effect","Possible mechanism of potentiative actions"]
["Positive regulation of drug transport or permeation","AZT (anti-HIV, HIV-1 reverse transcriptase inhibitor)","1,8-Cineole (formed hydrogen bonds with lipid head groups of stratum corneum lipids (1))","Enhanced cross-skin permeation of AZT (2)","Enabled drug transport across skin possibly by disrupting absorption barrier via binding to lipid head groups."]
[null,"Ciprofloxacin (antibacterial, inhibited DNA gyrase, an enzyme specific and essential for all bacteria)","Gatifloxacin (inhibited efflux pump of ciprofloxacin (3))","Synergistic antibacterial action against pseudomonas aeruginosa via efflux pump inhibition (3)","Avoided drug excretion by inhibiting efflux pump of ciprofloxacin."]
[null,"Doxorubicin (anticancer by DNA intercalation)","HPMA copolymer (formed conjugate with anthracycline (4))","Polymer anthracycline conjugation enabled bypass of multi-drug resistance (4)","Enabled drug absorption by avoiding its efflux via drug-polymer conjugate formation."]
[null,"Fexofenadine (nonsedating antihistamine, H1-antagonist, renal uptake by hOAT3 transporter)","Probenecid (inhibited hOAT3 transporter uptake of fexofenadine (5))","Increased plasma concentration of fexofenadine due to inhibition of its renal elimination (6)","Avoided drug excretion by inhibiting hOAT3 transporter uptake of fexofenadine."]
[null,"Levodopa (dopaminergic agent in Parkinson's disease)","Fatty acid synthesis inhibitor (selective inhibition of fatty acid synthesis delays barrier recovery rates after barrier perturbation of drugs (7))","Enhanced transcutaneous delivery of levodopa (7-9)","Delayed recovering of drug transport barrier by inhibiting the synthesis of barrier components."]
[null,"Low molecular weight heparin (antithrombotic, antithrombin binder to inhibit activated coagulation factors)","Chitosan (absorption enhancer, reversibly interacted with components of tight junctions, leading to widening of paracellular routes and increased permeability of peptide drugs across mucosal epithelia (10))","Oral drug absorption enhancement (10)","Disrupted drug absorption barrier across mucosal epithelia via interaction with barrier components."]
[null,"Low molecular weight heparin (antithrombotic, antithrombin binder to inhibit activated coagulation factors)","Sodium caprate (absorption enhancer, released calcium from intracellular stores via activation of phospholipase C in plasma membrane, which induced contraction of calmodulin-dependent actin microfilament, followed by dilatation of the paracellular route (11))","Sodium caprate acts as a relatively safe and efficient absorption enhancer of low molecular weight heparin (11-13)","Disrupted drug absorption barrier at plasma membrane."]
["Enhanced drug distribution or localization ","Fluorouracil (anticancer, metabolized by thymidine phosphorylase and others, metabolite inhibited thymidylate synthase that stopped DNA synthesis (14), metabolite stabilized P53 due to RNA-directed effects)","Sorivudine (antiviral, metabolized into (E)-5-(2-Bromovinyl)uracil by thymidine phosphorylase, which subsequently inactivates this enzyme by irreversible binding (15))","Enhanced toxic activity of fluorouracil by elevating its plasma concentrations (15)","Enhanced level of drug in plasma by metabolism and uptake inhibition."]
[null,"Cerivastatin (cholesterol-lowering, HMG-CoA reductase inhibitor)","Gemfibrozil (inhibited CYP2C8 mediated metabolism of statins, inhibited OATP2 mediated uptake of cerivastatin (16))","Increased plasma concentration of statins by inhibiting their metabolism and uptake (16-18)","Enhanced level of drug in plasma by metabolism and uptake inhibition."]
[null,"Cyclosporine (immunosuppressive via calcineurin antagonism, induced nephrotoxicity by decreasing renal blood flow, generating reactive free radicals, and inducing vasoconstriction and apoptosis)","Sirolimus (increased cyclosporine concentrations in whole blood and, particularly, in kidney (19))","Exacerbated renal dysfunction by cyclosporine (19)","Enhanced level of drug in tissue of toxic action."]
[null,"HSV thymidine kinase gene and ganciclovir (anticancer gene therapy drug combination)","Ponicidin (significantly accumulated the phosphorylated metabolites of ganciclovir and suppressed the extracellular release of ganciclovir (20))","Potentiated ganciclovir cytotoxicity (20)","Enhanced level of prodrug metabolite."]
[null,"Methamphetamine (psychomotor stimulant by targeting biogenic amine transporters)","D-chlorpheniramine (increased plasma and brain tissue concentrations of methamphetamine (21))","Significantly potentiated methamphetamine-induced psychomotor activation (21, 22)","Enhanced level of drug in tissue of therapeutic action."]
[null,"HSV thymidine kinase gene and ganciclovir (anticancer gene therapy drug combination)","Scopadulciol (stimulated HSV thymidine kinase activity, increased levels of ganciclovir metabolite (23))","Improved efficacy of cancer gene therapy via enhanced activity and increased level of prodrug metabolite (23)","Enhanced level of prodrug metabolite."]
[null,"Rosuvastatin (decreased levels of atherogenic lipoproteins in patients with or at high risk of cardiovascular disease, HMG-CoA inhibitor)","Cyclosporine (Inhibited OATP-C mediated uptake, rosuvastatin is a substrate of this process (24))","Significantly increased systemic exposure of rosuvastatin (24)","Enhanced level of drug by inhibiting drug uptake."]
[null,"Rosuvastatin (decreased levels of atherogenic lipoproteins in patients with or at high risk of cardiovascular disease, HMG-CoA inhibitor)","Gemfibrozil (Inhibited OATP2 mediated uptake, rosuvastatin is a substrate of this process (25))","Increased plasma concentrations of rosuvastatin (26)","Enhanced level of drug by inhibiting drug uptake."]
[null,"Ergotamine (5-HT1B/1D receptor agonist (27), agonist of presynaptic dopamine receptors and alpha 2-adrenoceptors, postsynaptic alpha 1 and alpha 2-adrenoceptors, and antagonist of the postsynaptic alpha 1-adrenoceptors (28))","Caffeine (adenosine receptor antagonist (29) that increased dopamine and GABAergic activities (30), cAMP-phosphodiesterase inhibitor (31))","Symptomatic treatment of chronic vascular headache by the combination (32)","Caffeine increased water solubility of ergotamine to enhance its absorption (33), producing potentiative effect. Possible synergy may occur at dopamine receptor that require further investigation."]
["Enhanced Drug metabolism ","Fluorouracil (anticancer, metabolized by thymidine phosphorylase and others (34), metabolite inhibited thymidylate synthase that stopped DNA synthesis (14), metabolite stabilized P53 due to RNA-directed effects (35))","2'-deoxyinosine (modulator that enhances thymidine phosphorylase activity (36))","Enhanced antitumor activity of fluorouracil in human colorectal cell lines and colon tumor xenografts (36)","Enhanced metabolism of prodrug into active metabolite."]
[null,"Doxorubicin (anticancer by DNA intercalation, converted to doxorubicinol by NADPH-dependent aldo/keto or carbonyl reductases (37), which produced cardiotoxicity by mediating transition from reversible to irreversible damage)","Paclitaxel (stimulated enzymatic activity of NADPH-dependent aldo/keto or carbonyl reductases (37))","Enhanced cardiotoxicity by increasing metabolism of doxorubicin into toxic metabolit (37)","Enhanced metabolism of drug into toxic metabolite."]
[null,"Tirapazamine and cisplatin (Tirapazamine produced anti-cancer effect and potentiated cisplatin anticancer activities when metabolized by P450R into toxic free radical (38), cisplatin is a DNA adduct)","Adenoviral delivery of human P450R genes (enhanced tirapazamine metabolizing enzyme expression and metabolism of prodrug into active metabolite (38))","Targeted gene prodrug therapy increased efficacy of tirapazamine (38)","Enhanced metabolism of prodrug into active metabolite."]
[]
["References:"]
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[2,"Narishetty ST & Panchagnula R (2004) Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. J Control Release 95(3):367-379."]
[3,"Pankey GA & Ashcraft DS (2005) In vitro synergy of ciprofloxacin and gatifloxacin against ciprofloxacin-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 49(7):2959-2964."]
[4,"Duncan R, Vicent MJ, Greco F, & Nicholson RI (2005) Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer. Endocr Relat Cancer 12 Suppl 1:S189-199."]
[5,"Tahara H, et al. (2006) Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid. Drug Metab Dispos 34(5):743-747."]
[6,"Nakajima Y, et al. (2004) Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats. Drug Metab Dispos 32(12):1383-1391."]
[7,"Tsai JC, et al. (1996) Metabolic approaches to enhance transdermal drug delivery. 1. Effect of lipid synthesis inhibitors. J Pharm Sci 85(6):643-648."]
[8,"Babita K & Tiwary AK (2005) Transcutaneous delivery of levodopa: enhancement by fatty acid synthesis inhibition. Mol Pharm 2(1):57-63."]
[9,"Koller WC & Rueda MG (1998) Mechanism of action of dopaminergic agents in Parkinson's disease. Neurology 50(6 Suppl 6):S11-14; discussion S44-18."]
[10,"Thanou M, Verhoef JC, & Junginger HE (2001) Oral drug absorption enhancement by chitosan and its derivatives. Advanced drug delivery reviews 52(2):117-126."]
[11,"Tomita M, Hayashi M, & Awazu S (1995) Absorption-enhancing mechanism of sodium caprate and decanoylcarnitine in Caco-2 cells. J Pharmacol Exp Ther 272(2):739-743."]
[12,"Motlekar NA, Srivenugopal KS, Wachtel MS, & Youan BB (2005) Oral delivery of low-molecular-weight heparin using sodium caprate as absorption enhancer reaches therapeutic levels. J Drug Target 13(10):573-583."]
[13,"Verhaeghe R (1998) The use of low-molecular-weight heparins in cardiovascular disease. Acta Cardiol 53(1):15-21."]
[14,"Pinedo HM & Peters GF (1988) Fluorouracil: biochemistry and pharmacology. (Translated from eng) J Clin Oncol 6(10):1653-1664 (in eng)."]
[15,"Kanamitsu SI, et al. (2000) Prediction of in vivo drug-drug interactions based on mechanism-based inhibition from in vitro data: inhibition of 5-fluorouracil metabolism by (E)-5-(2-Bromovinyl)uracil. Drug Metab Dispos 28(4):467-474."]
[16,"Shitara Y, Hirano M, Sato H, & Sugiyama Y (2004) Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther 311(1):228-236."]
[17,"Fujino H, et al. (2003) Studies on the interaction between fibrates and statins using human hepatic microsomes. Arzneimittelforschung 53(10):701-707."]
[18,"Prueksaritanont T, et al. (2002) Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 30(11):1280-1287."]
[19,"Podder H, et al. (2001) Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 12(5):1059-1071."]
[20,"Hayashi K, Hayashi T, Sun HD, & Takeda Y (2000) Potentiation of ganciclovir toxicity in the herpes simplex virus thymidine kinase/ganciclovir administration system by ponicidin. Cancer Gene Ther 7(1):45-52."]
[21,"Okuda T, et al. (2004) Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats. Eur J Pharmacol 505(1-3):135-144."]
[22,"Rothman RB, Blough BE, & Baumann MH (2006) Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction. Trends Pharmacol Sci 27(12):612-618."]
[23,"Hayashi K, et al. (2006) The role of a HSV thymidine kinase stimulating substance, scopadulciol, in improving the efficacy of cancer gene therapy. J Gene Med 8(8):1056-1067."]
[24,"Simonson SG, et al. (2004) Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clinical Pharmacology and Therapeutics 76(2):167-177."]
[25,"Yamazaki M, et al. (2005) Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Xenobiotica 35(7):737-753."]
[26,"Schneck DW, et al. (2004) The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 75(5):455-463."]
[27,"Villalon CM, et al. (1999) Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: role of 5-HT1B/1D receptors and alpha2-adrenoceptors. (Translated from eng) Br J Pharmacol 126(3):585-594 (in eng)."]
[28,"Badia A, Moron A, Cuffi L, & Vila E (1988) Effects of ergotamine on cardiovascular catecholamine receptors in the pithed rat. (Translated from eng) Gen Pharmacol 19(3):475-481 (in eng)."]
[29,"Boulenger JP, Patel J, & Marangos PJ (1982) Effects of caffeine and theophylline on adenosine and benzodiazepine receptors in human brain. (Translated from eng) Neurosci Lett 30(2):161-166 (in eng)."]
[30,"Mukhopadhyay S & Poddar MK (1995) Caffeine-induced locomotor activity: possible involvement of GABAergic-dopaminergic-adenosinergic interaction. (Translated from eng) Neurochem Res 20(1):39-44 (in eng)."]
[31,"Levin RM, Greenberg SH, & Wein AJ (1981) Quantitative analysis of the effects of caffeine on sperm motility and cyclic adenosine 3',5'-monophosphate (AMP) phosphodiesterase. (Translated from eng) Fertil Steril 36(6):798-802 (in eng)."]
[32,"Cohen SG & Criep LH (1949) Observations on the symptomatic treatment of chronic vascular headache with cafergone (ergotamine tartrate and caffeine). (Translated from eng) N Engl J Med 241(23):896-900 (in eng)."]
[33,"Anderson JR, Drehsen G, & Pitman IH (1981) Effect of caffeine on ergotamine absorption from rat small intestine. (Translated from eng) J Pharm Sci 70(6):651-657 (in eng)."]
[34,"Higley B, Oakes J, De Mello J, & Giles GR (1982) Pyrimidine nucleoside phosphorylase activity in tumour and matched normal gastrointestinal mucosa. Gut 23(12):1072-1076."]
[35,"Meyers M, Wagner MW, Hwang HS, Kinsella TJ, & Boothman DA (2001) Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res 61(13):5193-5201."]
[36,"Ciccolini J, et al. (2000) Enhanced antitumor activity of 5-fluorouracil in combination with 2'-deoxyinosine in human colorectal cell lines and human colon tumor xenografts. Clinical Cancer Research 6(4):1529-1535."]
[37,"Minotti G, et al. (2001) Paclitaxel and docetaxel enhance the metabolism of doxorubicin to toxic species in human myocardium. Clin Cancer Res 7(6):1511-1515."]
[38,"Cowen RL, et al. (2004) Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting cure. Cancer Res 64(4):1396-1402."]

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