הכנה לבחינות התמחות באונקולוגיה. טיפול תרופתי- תרופות ציטוטוקסיות: השפעות גומלין בין תרופתיות ובין תרופות לקרינה ערך: פרופ’ נ. חיים , יולי 2003, עודכן-ינואר 2004 כתובת לשאלות והערות : [email protected] Possible mechanisms of drug interactions. Synergism antagonism modulation
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Possible mechanisms include cisplatin-mediated enhanced DNA damage, and interference with repair of cisplatin-DNA adducts.
-increased FdUMP formation
-enhanced 5FU metabolism
-decreased 5FU clearance
Leucovorin stabilizes the
FdUdMP-TS-folate ternary complex
(a stable covalent complex with TS).
1. Uracil (in UFT): inhibits DPD
2. Eniluracil: a pyrimidine analog that lacks antitumor activity of its own; inactivates DPD by forming a covalent bond that permanently alters the active site of the enzyme. When given with oral 5FU inhibits degradation of 5FU within the GIT (and increases bioavailability to approximately 100%).
3. S1 : Oral formulation composed of ftorafur, 5-chloro-2,4-dihydropyridine (=reversible DPD inhibitor) and oxonic acid (protects from incorporation of 5FU metabolites into RNA of normal GIT tissue).
When given before 5FU, MTX-mediated inhibition of DHFR results in accumulation of PRPP. Increased availability of PRPP promotes formation of FUMPwith enhanced FUTP incorporation into RNA.
Masci G et al. J Clin Oncol 21:736-9,2003
Magagnoli M et al.Ann Oncol 14: 959-60,2003 (letter)
Okuda H et al. Drug metab dispos 25: 270-3, 1997:
-increased DNA damage
-inhibition of DNA repair
-accumulation of cells in S phase
Leucovorin (tetrahydrofolate) is antagonist of methotrexate
Blum R et al. Ann Oncol 13: 327-30, 2002
Shamash J et al. Ann Oncol 14: 169-70, 2002 (letter)
Interaction between methotrexate /, sulphonamides, and phenytoin:
Increased toxicity of MTX due to protein-binding displacement by these drugs.
Thought to be mainly due to an increase in platinum DNA adduct formation, which in turn results from dFdC incorporation into DNA.
Synergistic action.frequently used in combination.
Prior administration of paclitaxel reduces doxorubicin clearance due to inhibition of doxorubicin liver clearance (possibly competition for biliary excretion of taxanes and anthracyclines mediated by p-gp).
Gianni L et al. J Clin Oncol 15: 1906-15, 1997
Gianni L et al. Ann Oncol 12: 1067-73, 2001
Inducers of cytochrome P-450 mixed function oxidases (anticonvulsants,e.g. phenytoin, phenobarbital): theoretically, accelerated metabolism and increased clearance
(same interaction is ,theoretically, possible with etoposide, doxorubicin, irinotecan)
(same interaction is, theoretically, possible with etoposide, doxorubicin, irinotecan)
Kearns CM & Egorin MJ. Semin Oncol 24: s2-91-s2-96, 1997
Belani CP et al. J Clin Oncol 17: 676-684, 1999
Seidman A et al. J Clin Oncol 20: 1215-21, 2002
Petrylak DP et al. J Clin Oncol 17: 958-67,1999
(Malingre MM et al. J Clin Oncol 19: 1160-6, 2001) or oral paclitaxel (Kruijtzer CMF et al.J Clin Oncol 20: 4508-16, 2002).
(In addition,cyclosporine is a substrate to P450 isoenzymes,which in the liver are responsible for the first pass elimination of taxanes, and therefore, contribute to the low bioavailability).
Altorki NK et al. J Clin Oncol 21: 2645-50, 2003
Dmitrovsky E. J Clin Oncol 21: 2631-2, 2003 (Editorial)
And with drugs which cause induction of cytochrome P-450...Vecht CJ. Lancet Neurol 2: 404-9, 2003 (review): (interactions with antiepileptic drugs can cause insufficient tumor and seizure control)., Villikka K et al. Clin Pharmacol Ther 66: 589-93, 1999 (CYTP3A4-inducing antiepileptics increase the clearance of vincristine).
Vincristine increases, in-vitro, accumulation of methotrexate in tumor cells (vinca-alkaloid induced blockade of drug efflux). In-vivo?
Rodman JH et al. J Clin Oncol 12: 2390-7, 1994
Possible (theoretical) interaction as with taxanes or vinca alkaloids
Kuhn JG. Oncology (Huntingt) 16: 33- 40, 2002 (influence of anticonvulsants)
Haaz MC et al. Cancer Res 58:468-72,1998
Kehrer DF et al. et al. J Clin Oncol 20: 3122-9, 2002
Potential but of unknown clinical significance interaction with CYP450 enzyme activity inducers (e.g. barbiturates) or blockers (e.g. glucocorticoids).
Kruijtzer CM et al. Ann Oncol 14: 197-204, 2003
cisplatin & carmustine (BCNU)
carmustine, vinblastine, methotrexate combination
cisplatin, vinblastine, bleomycin combination (impaired bioavailability)