TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE ANDHYGIENE (1993) 87, 303 303 1 Short Report1 The potential of desipramine to reverse chloroquine resistance of Plasmodium falciparum is reduced by its binding to plasma protein Matthew K. Boulterl, Patrick G. Bray’, Robert E. Howells and Stephen A. WardI, ‘Tropical Pharmacology Unit, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 SQA, UK; 2The Wellcome Trust, 1 Park Square West, London, NW1 4LJ, UK; 3Department of Pharmacology and Therapeutics, The University of Liverpool, P.O. Box 147, Liverpool, L69 3BX, UK The rapid spread of resistanceto chloroquine (CQ) has prompted the investigation of agents which demonstrate the ability to reverse chloroquine resistance in Plasmo- dium falciparum in vitro. A number of these agents has been examined and of particular interest is the debate over the choice of cyproheptadine (CYP) or desipramine (DES) for use in clinical situations. Although DES is ef- fective in vitro(BITONT1& MCCANN, 1989; PETERS et al., 1989), WARSAME et al. (1992) recently reported that it produced no such reversal in vivo during a clinical trial in Somalia. We believe that a possible explanation for this result could be related to the effective removal of desi- pramine from the circulation due to plasma protein bind- ing. Reported data demonstrate that DES is 90% bound in circulating human olasma of healthv individuals (SJOKVIST, lg71). - We have examined the resistancereversing potential in vitro of both DES and CYP in the nresenceand absence of albumin and al-acid glycoprot&n at concentrations typically found in the plasma of a malarious patient (MANSOR et al., 1991). Sensitivity in vitro of the Kl (CQ resistant) strain of P. faZciparum was assessed using a modification of the semi-automated microdilution tech- nique of DESJARDINS et al. (1979). We determined the effect of plasma proteins on the CQ dose responsecurves in the presenceand absence of DES and CYP at 300 nM. This concentration represents a clinically feasible plasma level for both drugs (PETERS et al., 1989; SJOKVIST, 1971). The results shown in the Figure are expressed in terms of activity enhancement index (AEI); AEI=ICso CQ ACTIVITY ENHANCEMENT INDEX 2.69 CYP DES -CONTROL m + PLASMA PROTEINS Figure. Activity enhancement index for cyproheptadine (CYP) and desi- pramine (DES) in the presence and absence of plasma proteins. alone/ICso CQ+putative reversing agent. Concurrent with reported data (BITONTI & MCCANN, 1989; PETERS et al., 1989; SALAMA & FACER, 1990), both CYP and DES produced a noticable reversal of CQ resistance. CYP produced a greater degree of reversal, with an AEI of 2.69 compared to one of 1.92 with DES. In the presence of plasma proteins the reversing effect of both drugs was reduced, with a far greater reduction seenwith DES: 73% compared to 33% with CYP. Our results demonstrated that the ability of DES to reverse CQ re- sistance is reduced by the presence of plasma protein in the assaysystem. This could be attributed to the well es- tablished fact that, in the presence of proteins, the amount of unbound DES is the determinant factor in erythrocyte uptake of the drug (JAVAID et al,., 1985). In addition, the extensive plasma protein bindmg of DES has been demonstrated to be largely due to binding to ~1. acid glycoprotein (SUZUKI et al., 1985). The levels of this protein have been reported to be 2-fold higher in the plasma of malarious patients compared to non-infected subjects (MANSOR et aZ., 1991). As a result, the amount of free drug available for entry into erythrocytes, and therefore available to reverse resistance, is likely to be even further reduced. Our data suggest that CYP may be a more suit- able choice of resistance reversal agent, in view of its greater efficacy and the reduced possibility of plasma protein binding. Furthermore, these results highlight the need to consider host-dependent factors when extrapolat- ing in vitro findings to in vivo situations. Acknowledgement This work was supported by a grant from the Wellcome Trust. References Bitonti. A. 1. & McCann. I’. P. (1989). Desioramine and cvoro- heotadine for reversal of chioroa&ne resistance in &mo- d&m falciparum. Lancet, ii, 1282-i283. Desjardins, R. E., Canfield, C. J., Haynes, J. D. & Chulay, J. D. (1979). Quantitative assessment of antimalarial activitv in vitro by a semi-automated microdilution technique. A&- microbial Agents and Chemotherapy, 16,710-718. Javaid, J. I., Davis, J. M. & Maiorano, M. (1985). Uptake and/or binding of tricyclic antidepressants in human red cells. Life Sciences, 36, 1761-1769. Mansor, S. M., Molyneux, M. E., Taylor, T. E., Ward, S. 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Warsame, M., Wernsdorfer, W. H. & Bjarkman, A. (1992). Lack of effect of desipramine on the response to chloroquine of patients with chloroquine-resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hy- giene, 86,235-236. Received 10 August 1992; accepted for publication 24 August I992