Effect of cisplatin and paclitaxel on plasma free tryptophan levels. An in vitro study.
Emesis is a common side effect of some antineoplastic drugs. Cisplatin (CP) induces a biphasic pattern of emesis referred to as acute (AE) and delayed (DE) emesis. The serotonergic system plays a major role in the pathogenesis of CP-induced AE, as suggested by the therapeutic efficacy of 5HT3 receptor antagonists. The pathogenesis of CP-induced DE are not clear. To date, there are no pharmacological agents which satisfactorily control DE. We hypothesize that increased availability of tryptophan (TRP) for the synthesis of brain serotonin (5-HT) could, at least in part, contribute to CP-induced DE. In fact, within 2-4 hrs of administration, CP is largely bound to albumin (ALB) with consequent possible displacement of TRP which circulates in plasma mostly (90% of total plasma TRP) bound to its natural carrier, ALB. To test this hypothesis, we studied in vitro the effect of increasing doses of cisplatin on F-TRP in plasma obtained from healthy volunteers. We also tested the effects of therapeutic amounts of paclitaxel, an antineoplastc agent which does not cause emesis.


RESULTS
F-TRP concentrations increased in a dose-dependent manner following incubation with cisplatin, in contrast to paclitaxel (PTX).


CONCLUSIONS
The preliminary data obtained suggest that CP, but not PTX, at therapeutic doses, increases plasma F-TRP concentrations. This increase has likely negligible relevance in CP-induced AE, which is induced by the 5-HT released by the enterochromaffin cell system, while it might play a role in the pathogenesis of CP-induced DE. In fact, CP binding to ALB is stable for 4-5 days following administration, thus suggesting long-term TRP displacement from ALB and enhanced brain 5-HT synthesis and release. Whether increased TRP availability for 5-HT synthesis might be the pathogenic mechanism for CP-induced DE in vivo, is currently being tested.
Muscaritoli
M
M
Department of Clinical Medicine, University La Sapienza, Rome, Italy. muscaritoli@uniroma1.it
Peverini
P
P
Cascino
A
A
Cangiano
C
C
Fanfarillo
F
F
Russo
M
M
Fava
A
A
Rossi Fanelli
F
F
D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D017239:Paclitaxel / Q000494:pharmacology*; D010949:Plasma / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D012709:Serum Albumin / Q000378:metabolism; D014364:Tryptophan / Q000097:blood*
D012709:Serum Albumin; D014364:Tryptophan; D017239:Paclitaxel; D002945:Cisplatin