EFFECTS OF CO-TRIMOXAZOLE CO-ADMINISTRATION ON THE PHARMACOKINETICS OF AMODIAQUINE IN HEALTHY VOLUNTEERS
Keywords:
Amodiaquine, Desethylamodiaquine, Co-trimoxazole, Pharmacokinetics, CYP2C8Abstract
Objectives: Amodiaquine (AQ) is a 4-aminoquinoline antimalarial drug that is rapidly and extensively metabolized mainly by CYP2C8 enzyme to N-desethylamodiaquine (DEAQ). Co-trimoxazole (CTZ) is a combination (sulfamethoxazole and trimethoprim) antimicrobial agent with the trimethoprim component being a potent inhibitor of CYP2C8. AQ and CTZ are likely to be co-administered in the treatment of patients with malaria and susceptible bacterial infections. This study evaluates the effect of CTZ co-administration on the pharmacokinetics of AQ.
Methods: In an open, two-way crossover study, 16 healthy volunteers were randomized to receive 600 mg single oral dose of AQ with or without the eleventh dose of CTZ (960 mg every 12 h for 7 days.) Blood samples were collected at pre-determined time intervals and analyzed for AQ and its major metabolite, DEAQ using a validated HPLC method.
Results: Co-administration of AQ and CTZ resulted in significant increases in the total area under the concentration–time curve (AUCT), maximum plasma concentration (Cmax) and terminal elimination half-life (T½) of AQ compared with values with AQ dosing alone (AUCT:234.36±57.21 vs 366.42±62.48 h ng/ml; Cmax:24.86±7.28 vs 40.28±11.15 ng/ml; T½: 6.49±3.56 vs 9.24±2.97 h), while the oral plasma clearance markedly decreased (3862.66±756.38 vs 2654.28±650.12 L/h). Co-administration also led to a pronounced decrease in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant decreases in Cmax and AUC of the metabolite.
Conclusion: Study evaluated for the first time the effect of CTZ co-administration on the pharmacokinetics of AQ in healthy adult volunteers. CTZ significantly increased AQ exposure and decreased plasma levels of the active metabolite DEAQ.
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Evans WE, McLeod HL. Pharmacogenomics–drug disposition, drug targets, and side effects. N Engl J Med 2003;348:538–49.
Lin JH, Lu AY. Inhibition and induction of Cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998;35:361-90.
Totah RA, Rettie AE. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 2005;77:341-52.
Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002;72:685-91.
Honkalammi J, Niemi M, Neuvonen PJ, Backman JT. Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab Dispos 2011;39:1977-86.
Niemi M, Kajosaari LI, Neuvonen M, Backman JT, Neuvonen PJ. The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004;57:441-7.
Neftel KA, Woodtly W, Schmid M, Frick PG, Fehr J. Amodiaquine induced agranulocytosis and liver damage. Br Med J 1986;292:721–3.
Churchill FC, Mount DL, Patchen LC, Bjorkman A. Isolation, characterization and standardization of a major metabolite of amodiaquine by chromatographic and spectroscopic methods. J Chromatogr B 1986;377:307–18.
Li XQ, Bjorkman A, Andersson TB, Ridderstrom M, Masimirembwa CM. Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther 2002;300:399-407.
Spencer HC, Oloo AJ, Watkins WW, Sixsmith DG, Churchilll FC, Koech DK. Amodiaquine more effective than chloroquine against Plasmodium falciparum malaria on Kenya Coast. Lacet 1984;1:956-7.
Juliana MS, Olivia T. Protecting the malarial drug arsenal: halting the rise and spread of amodiaquine resistance by monitoring the PFCRT, SVMNT type. Mal J 2010;9:374.
Salako LA, Idowu OR. Failure to detect amodiaquine in the blood after oral administration. Br J Clin Pharmacol 1985;20:307-11.
Churchill FC, Patchen LC, Campbell CC, Schwartz IL, Nguyen-Dinh P, Dickinson CM. Amodiaquine as a prodrug: importance of metabolite(s) in the antimalarial effect of amodiaquine in humans. Life Sci 1985;36:53-62.
Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpin K, et al. Co-trimoxazole as prophylaxis against opportunistic infections as HIV-infected Zambian children (CHAP): a chap a double-blind randomized placebo-controlled trial. Lancet 2004;364:1865-71.
Belle LL, Sharon S, Makrides V, Gambertoglio JG. Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with Human Immunodeficiency Virus infection. Antimicrob Agents Chemother 1996;40:1231-6.
Moore KH, Yuen GJ, Raasch RH, Eron JJ, Martin D, Mydlow PK, et al. Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin Pharmacol Ther 1996;59:550-8.
Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically significant drug interactions with cyclosporin. An update. Clin Pharmacokinet 1996;30:141-79.
Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ. Trimethoprim and sulfamethxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab Dispos 2002;30:631-5.
Gitau EN, Muchohi SN, Ogutu BR, Githiga LM, Kokwaro GO. Selective and sensitive liquid chromatographic assay of amodiaquine and desethylamodiaquine in whole blood spotted on filter paper. J Chromatogr B: Anal Technol Biomed Life Sci 2004;799:173-7.
Winstanley PA, Edwards G, Orme M, Breckinridge AM. The disposition of amodiaquine in man after oral administration. Br J Clin Pharmacol 1987;23:1–7.
Hietala SF, Bhattarai A, Msellem M, Roshammar D, Ali AS, Stromberg J, et al. Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria. J Pharmacokinet Pharmacodyn 2007;34:669–86.
Soyinka JO, Odunfa O, Ademisoye AA. Effects of food on the pharmacokinetics of amodiaquine in healthy volunteers. AJPRHC 2011;3:109-13.
Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF. The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br J Clin Pharmacol 2005;59:70-9.
Hayeshi R, Masimirembwa C, Mukanganyama S, Ungell B. Lysosomal trapping of amodiaquine: impact on transport across intestinal epithelia models. Biopharm Drug Dispos 2008;29:324–34.
Villani P, Viale P, Signorini B, Cadeo B, Marchetti F, Villani A, et al. Pharmacokinetic evaluation of oral levofloxacin in human immunodeficiency virus-infected subjects receiving concomitant antiretroviral therapy Antimicrob Agents Chemother 2001;45:2160-2.
Soyinka JO, Onyeji CO. Alteration of pharmacokinetics of proguanil in healthy volunteers following concurrent administration of efavirenz. Eur J Pharm Sci 2010;39: 213-8.
Winstanley PA, Edwards G, Orme ML, Breckenridge AM. Effect of dose size on amodiaquine pharmacokinetics after oral administration. Eur J Clin Pharmacol 1987;33:331–3.
Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 2007;82:197-203.
Soyinka JO, Onyeji CO, Nathaniel TI, Odunfa OO, Ebeshi BU. Effects of concurrent administration of efavirenz on the disposition kinetics of amodiaquine in healthy volunteers. J Pharm Res 2013;6:275-9.