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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacokinetically reductive drug combinations."]
["Reductive effect has been determined by established methods and its molecular mechanism has been revealed."]
[]
["Biochemical class of reductive effect ","Drug A (therapeutic or toxic effects and mechanism of actions)","Drug B (mechanism of action related to reductive effect)","Reported reductive effect","Possible mechanism of reductive actions"]
["Drug transport and permeation ","Amphotericin B (antileishmanial, formed aggregate with miltefosine (1))","Miltefosine (antileishmanial, formed aggregate with amphotericin B (1))","Reduced miltefosine-induced paracellular permeability enhancement in Caco-2 cell monolayers, inhibited uptake of both drugs, decreased transepithelial transport of both drugs (2)","Reduced drug permeability and transport."]
[null,"Gamma-hydroxybutyrate (drug of abuse, increased dopamine concentration, MCT1 transporter mediated its disposition and renal reabsorption (3))","Luteolin (exhibited MCT1 transporter mediated uptake of gamma-hydroxybutyrate (4))","Significantly increased renal and total clearances of gamma-hydroxybutyrate (3)","Enhanced drug excretion."]
["Drug distribution and localization ","Cisplatin (DNA inter- and intra- strand adduct)","Procainamide hydrochloride (formed cisplatin-procainamide complex (5))","Reduced cisplatin-induced hepatotoxicity via formation of less toxic platinum complex, leading to inactivation of cisplatin or its highly toxic metabolites and to a different subcellular distribution of platinum (5)","Reduced level of toxic drug by formation of less toxic complex and rearrangement of its subcellular distribution."]
["Drug metabolism ","Warfarin (anticoagulant and antithrombotic, affected coagulation proteins that act sequentially to produce thrombin, metabolized by CYP3A4 (6))","Quinidine (stimulated CYP3A4 mediated metabolism of warfarin (7))","Reduced anticoagulanet effect of warfarin by stimulating its metabolism (7)","Enhanced metabolism of active drug into inactive metabolite."]
[null,"Diclofenac (anti-inflammatory, metabolized into 5-hydroxylated by cytochrome P450 CYP3A4 (8))","Quinidine (stimulated CYP3A4 mediated metabolism of diclofenac (8))","Increased diclofenac clearance and reduced its plasma concentration by enhanced metabolism (8)","Reduced level of drug by enhanced metabolism."]
[null,"Mycophenolate mofetil (immunosuppressive, a prodrug whose metabolite mycophenolic acid is a potent and reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase, metabolized by gastrointestinal uridine diphosphate-glucuronosyltransferases (9))","Rifampin (induced expression of gastrointestinal uridine diphosphate-glucuronosyltransferases (10))","Drug interaction leads to underexposure and loss of clinical efficacy of mycophenolate mofetil by induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters (10)","Reduced level of drug by enhanced metabolism."]
[null,"Valproic acid (antiepileptic, increased gabaergic transmission, reduced release and/or effects of excitatory amino acids, blocked voltage-gated sodium channels, modulated dopaminergic and serotoninergic transmission, metabolized into valproic acid glucuronide (11))","Carbapenem antibiotics (inhibited the hydrolytic enzyme involved in the hydrolysis of valproic acid glucuronide to valproic acid, resulting in a decrease of plasma concentration of valproic acid (12))","Caused seizures in epileptic patients due to lowered plasma levels of valproic acid (12, 13) ","Reduced level of drug in plasma by metabolism inhibition."]
[]
["References:"]
[1,"Menez C, Legrand P, Rosilio V, Lesieur S, & Barratt G (2007) Physicochemical characterization of molecular assemblies of miltefosine and amphotericin B. Mol Pharm 4(2):281-288."]
[2,"Menez C, et al. (2006) Interaction between miltefosine and amphotericin B: consequences for their activities towards intestinal epithelial cells and Leishmania donovani promastigotes in vitro. Antimicrob Agents Chemother 50(11):3793-3800."]
[3,"Wang Q, Lu Y, & Morris ME (2007) Monocarboxylate transporter (MCT) mediates the transport of gamma-hydroxybutyrate in human kidney HK-2 cells. Pharm Res 24(6):1067-1078."]
[4,"Wang Q & Morris ME (2007) Flavonoids modulate monocarboxylate transporter-1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo. Drug Metab Dispos 35(2):201-208."]
[5,"Zicca A, et al. (2002) Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats. Eur J Pharmacol 442(3):265-272."]
[6,"Kaminsky LS & Zhang ZY (1997) Human P450 metabolism of warfarin. Pharmacol Ther 73(1):67-74."]
[7,"Ngui JS, et al. (2001) In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4'- and 10-hydroxywarfarin. Drug Metab Dispos 29(6):877-886."]
[8,"Ngui JS, et al. (2000) Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine. Drug Metab Dispos 28(9):1043-1050."]
[9,"Mackenzie PI (2000) Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid. Ther Drug Monit 22(1):10-13."]
[10,"Kuypers DR, Verleden G, Naesens M, & Vanrenterghem Y (2005) Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther 78(1):81-88."]
[11,"Dickinson RG, Hooper WD, & Eadie MJ (1984) pH-dependent rearrangement of the biosynthetic ester glucuronide of valproic acid to beta-glucuronidase-resistant forms. Drug Metab Dispos 12(2):247-252."]
[12,"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."]
[13,"Perucca E (2002) Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 16(10):695-714."]

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