View More View Less
  • 1 Semmelweis Egyetem, Általános Orvostudományi Kar II. Gyermekgyógyászati Klinika Budapest Tűzoltó u. 7–9. 1094
  • | 2 Országos Onkológiai Intézet Budapest
Open access

Cross Mark

A kemoterápiás szerek farmakokinetikai paramétereinek pontos monitorozása elengedhetetlen, hiszen számos mellékhatással járhatnak. Célkitűzés: Nagy dózisú methotrexatkezelések farmakokinetikájának és toxicitásának vizsgálata akut lymphoid leukaemiás gyermekekben. Betegek és módszerek: ALL-BFM 1995 és 2002 protokollok szerinti 5 g/m2/24 óra dózisú methotrexatkezelésre 43 gyermeknél (28 fiú, 15 lány, átlagéletkor 7,03 év) 147 esetben került sor. A methotrexat- és 7-hidroxi-methotrexat-szint-meghatározást nagy nyomású folyadékkromatográfiával végezték a szerzők az infúzió beadását követő 24., 36., 48. órában. Vizsgálták a fellépő máj- és vesetoxicitást, vérképet, a grade III/IV mucositis kialakulását. Eredmények: A methotrexat koncentrációja az esetek 72,5%-ában a terápiás tartományba (30–100 µmol/l) esett. Az ismételt kezelések hasonló methotrexatszinteket eredményeztek. Hepatotoxicitás 17%-ban, hypoproteinaemia 48,9%-ban fordult elő a kezeléseket követően. Szignifikáns korreláció állt fent a 7-hidroxi-methotrexat- és a szérumkreatinin-szintek között (p<0,05). Következtetések: Az 5 g/m2 dózisú kezeléseket követően megbízhatóan lehetett a terápiás szérumszinteket biztosítani. A kialakult mellékhatások enyhék és reverzíbilisek voltak. A 7-hidroxi-methotrexat-szintek monitorozása talán hasznosabb a methotrexatszintekénél. Orv. Hetil., 2011, 152, 1609–1617.

  • Török Sz., Borgulya G., Schuler D.: A gyermekkori rosszindulatú daganatok gyakoriságának és túlélési mutatóinak változásai 1988 és 1997 között az Országos Gyermektumor Regiszter adatai alapján. Orv. Hetil., 2001, 142, 1211–1215.

    Schuler D. , 'A gyermekkori rosszindulatú daganatok gyakoriságának és túlélési mutatóinak változásai 1988 és 1997 között az Országos Gyermektumor Regiszter adatai alapján ' (2001 ) 142 Orv. Hetil. : 1211 -1215.

    • Search Google Scholar
  • Török Sz.: Gyermekkori daganatos megbetegedések hazai előfordulási gyakorisága és mentálhigiénés szemléletű rehabilitációja. Doktori értekezés, 2006. Semmelweis Egyetem 5. számú Doktori Iskola, Témavezető: Tomcsányi Teodóra.

  • Walling, J.: From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates. Invest. New Drugs, 2006, 24, 37–77.

    Walling J. , 'From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates ' (2006 ) 24 Invest. New Drugs : 37 -77.

    • Search Google Scholar
  • Panetta, J. C., Sparreboom, A., Pui, C. H. és mtsai: Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells. PLoS Comput. Biol., 2010, 6, e1001019.

    Pui C. H. , 'Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells ' (2010 ) 6 PLoS Comput. Biol. : e1001019 -.

    • Search Google Scholar
  • Treon, S. P., Chabner, B. A.: Concepts in use of high-dose methotrexate therapy. Clin. Chem., 1996, 42 (8 Pt 2), 1322–1329.

    Chabner B. A. , 'Concepts in use of high-dose methotrexate therapy ' (1996 ) 42 Clin. Chem. : 1322 -1329.

    • Search Google Scholar
  • Schmiegelow, K.: Advances in individual prediction of methotrexate toxicity: a review. Br. J. Haematol., 2009, 146, 489–503.

    Schmiegelow K. , 'Advances in individual prediction of methotrexate toxicity: a review ' (2009 ) 146 Br. J. Haematol. : 489 -503.

    • Search Google Scholar
  • Groninger, E., Proost, J. H., de Graaf, S. S.: Pharmacokinetic studies in children with cancer. Crit. Rev. Oncol. Hematol., 2004, 52, 173–197.

    Graaf S. S. , 'Pharmacokinetic studies in children with cancer ' (2004 ) 52 Crit. Rev. Oncol. Hematol. : 173 -197.

    • Search Google Scholar
  • Yarlagadda, S. G., Perazella, M. A.: Drug-induced crystal nephropathy: an update. Expert Opin. Drug Saf., 2008, 7, 147–158.

    Perazella M. A. , 'Drug-induced crystal nephropathy: an update ' (2008 ) 7 Expert Opin. Drug Saf. : 147 -158.

    • Search Google Scholar
  • Cheng, K. K.: Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer. Eur. J. Cancer Care (Engl.), 2008, 17, 306–311.

    Cheng K. K. , 'Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer ' (2008 ) 17 Eur. J. Cancer Care (Engl.) : 306 -311.

    • Search Google Scholar
  • Titier, K., Lagrange, F., Pehourcq, F. és mtsai: Pharmacokinetic interaction between high-dose methotrexate and oxacillin. Ther. Drug Monit., 2002, 24, 570–572.

    Pehourcq F. , 'Pharmacokinetic interaction between high-dose methotrexate and oxacillin ' (2002 ) 24 Ther. Drug Monit. : 570 -572.

    • Search Google Scholar
  • Magyarossy A. és a Magyar Gyermekorvos Társaság Gyermekonkológiai Szekciója: A gyermekkori akut limfoblasztos leukémia kezelésében elért hazai eredmények. Magy. Onkol., 2000, 44, 255–259.

    Magyarossy A. , 'A gyermekkori akut limfoblasztos leukémia kezelésében elért hazai eredmények ' (2000 ) 44 Magy. Onkol. : 255 -259.

    • Search Google Scholar
  • Trevino, L. R., Shimasaki, N., Yang, W. és mtsai: Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J. Clin. Oncol., 2009, 27, 5972–5978.

    Yang W. , 'Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects ' (2009 ) 27 J. Clin. Oncol. : 5972 -5978.

    • Search Google Scholar
  • Pauley, J. L., Panetta, J. C., Schmidt, J. és mtsai: Late-onset delayed excretion of methotrexate. Cancer Chemother. Pharmacol., 2004, 54, 146–152.

    Schmidt J. , 'Late-onset delayed excretion of methotrexate ' (2004 ) 54 Cancer Chemother. Pharmacol. : 146 -152.

    • Search Google Scholar
  • Xu, W., Tang, Y., Song, H. és mtsai: Retrospective study on elimination delay of methotrexate in high-dose therapy of childhood acute lymphoblastic leukemia in China. J. Pediatr. Hematol. Oncol., 2007, 29, 688–693.

    Song H. , 'Retrospective study on elimination delay of methotrexate in high-dose therapy of childhood acute lymphoblastic leukemia in China ' (2007 ) 29 J. Pediatr. Hematol. Oncol. : 688 -693.

    • Search Google Scholar
  • Plard, C., Bressolle, F., Fakhoury, M. és mtsai: A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother. Pharmacol., 2007, 60, 609–620.

    Fakhoury M. , 'A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia ' (2007 ) 60 Cancer Chemother. Pharmacol. : 609 -620.

    • Search Google Scholar
  • Wysocki, M., Krzyzanowski, M., Ozynski, T. és mtsai: Studies of methotrexate pharmacokinetics in children with neoplasms of the hematopoietic system after administration of different doses of the drug. Acta Haematol. Pol., 1992, 23, 179–183.

    Ozynski T. , 'Studies of methotrexate pharmacokinetics in children with neoplasms of the hematopoietic system after administration of different doses of the drug ' (1992 ) 23 Acta Haematol. Pol. : 179 -183.

    • Search Google Scholar
  • Evans, W. E., Crom, W. R., Abromowitch, M. és mtsai: Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N. Engl. J. Med., 1986, 314, 471–477.

    Abromowitch M. , 'Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect ' (1986 ) 314 N. Engl. J. Med. : 471 -477.

    • Search Google Scholar
  • Woessmann, W., Seidemann, K., Mann, G. és mtsai: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood, 2005, 105, 948–958.

    Mann G. , 'The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95 ' (2005 ) 105 Blood : 948 -958.

    • Search Google Scholar
  • Wiela-Hojenska, A., Gorczynska, E., Orzechowska-Juzwenko, K. és mtsai: Metabolic functions of the liver during chemotherapy in children with acute lymphoblastic leukemia. Int. J. Clin. Pharmacol. Ther., 2001, 39, 246–250.

    Orzechowska-Juzwenko K. , 'Metabolic functions of the liver during chemotherapy in children with acute lymphoblastic leukemia ' (2001 ) 39 Int. J. Clin. Pharmacol. Ther. : 246 -250.

    • Search Google Scholar
  • Erttmann, R., Bielack, S., Landbeck, G.: Kinetics of 7-hydroxy-methotrexate after high-dose methotrexate therapy. Cancer Chemother. Pharmacol., 1985, 15, 101–104.

    Landbeck G. , 'Kinetics of 7-hydroxy-methotrexate after high-dose methotrexate therapy ' (1985 ) 15 Cancer Chemother. Pharmacol. : 101 -104.

    • Search Google Scholar
  • Borsi, J. D., Sagen, E., Romslo, I. és mtsa: Comparative study on the pharmacokinetics of 7-hydroxy-methotrexate after administration of methotrexate in the dose range of 0.5–33.6 g/m2 to children with acute lymphoblastic leukemia. Med. Pediatr. Oncol., 1990, 18, 217–224.

    Romslo I. , 'Comparative study on the pharmacokinetics of 7-hydroxy-methotrexate after administration of methotrexate in the dose range of 0.5–33.6 g/m2 to children with acute lymphoblastic leukemia ' (1990 ) 18 Med. Pediatr. Oncol. : 217 -224.

    • Search Google Scholar
  • Buitenkamp, T. D., Mathot, R. A., de Haas, V. és mtsai: Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica, 2010, 95, 1106–1113.

    Haas V. , 'Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia ' (2010 ) 95 Haematologica : 1106 -1113.

    • Search Google Scholar
  • Maiguma, T., Hayashi, Y., Ueshima, S. és mtsai: Relationship between oral mucositis and high-dose methotrexate therapy in pediatric acute lymphoblastic leukemia. Int. J. Clin. Pharmacol. Ther., 2008, 46, 584–590.

    Ueshima S. , 'Relationship between oral mucositis and high-dose methotrexate therapy in pediatric acute lymphoblastic leukemia ' (2008 ) 46 Int. J. Clin. Pharmacol. Ther. : 584 -590.

    • Search Google Scholar
  • Skarby, T., Jonsson, P., Hjorth, L. és mtsai: High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother. Pharmacol., 2003, 51, 311–320.

    Hjorth L. , 'High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL) ' (2003 ) 51 Cancer Chemother. Pharmacol. : 311 -320.

    • Search Google Scholar
  • Hempel, L., Misselwitz, J., Fleck, C. és mtsai: Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function. Med. Pediatr. Oncol., 2003, 40, 348–354.

    Fleck C. , 'Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function ' (2003 ) 40 Med. Pediatr. Oncol. : 348 -354.

    • Search Google Scholar
  • Joannon, P., Oviedo, I., Campbell, M. és mtsa: High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance. Pediatr. Blood Cancer, 2004, 43, 17–22.

    Campbell M. , 'High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance ' (2004 ) 43 Pediatr. Blood Cancer : 17 -22.

    • Search Google Scholar
  • Borsi, J. D., Sagen, E., Romslo, I. és mtsai: 7-hydroxymethotrexate concentrations in serum and cerebrospinal fluid of children with acute lymphoblastic leukemia. Cancer Chemother. Pharmacol., 1990, 27, 164–167.

    Romslo I. , '7-hydroxymethotrexate concentrations in serum and cerebrospinal fluid of children with acute lymphoblastic leukemia ' (1990 ) 27 Cancer Chemother. Pharmacol. : 164 -167.

    • Search Google Scholar
  • Evans, W. E., Christensen, M. L.: Drug interactions with methotrexate. J. Rheumatol. Suppl., 1985, 12, (Suppl. 12), 15–20.

    Christensen M. L. , 'Drug interactions with methotrexate ' (1985 ) 12 J. Rheumatol. Suppl. : 15 -20.

    • Search Google Scholar
  • Liegler, D. G., Henderson, E. S., Hahn, M. A. és mtsa: The effect of organic acids on renal clearance of methotrexate in man. Clin. Pharmacol. Ther., 1969, 10, 849–857.

    Hahn M. A. , 'The effect of organic acids on renal clearance of methotrexate in man ' (1969 ) 10 Clin. Pharmacol. Ther. : 849 -857.

    • Search Google Scholar
  • Paxton, J. W.: Interaction of probenecid with the protein binding of methotrexate. Pharmacology, 1984, 28, 86–89.

    Paxton J. W. , 'Interaction of probenecid with the protein binding of methotrexate ' (1984 ) 28 Pharmacology : 86 -89.

    • Search Google Scholar
  • Gewirtz, D. A., Holt, S. A.: Protein binding as a component of drug interaction in cellular pharmacokinetic studies. Effects of probenecid on transport and accumulation of methotrexate in Ehrlich ascites tumor cells in vitro. Biochem. Pharmacol., 1985, 34, 747–754.

    Holt S. A. , 'Protein binding as a component of drug interaction in cellular pharmacokinetic studies. Effects of probenecid on transport and accumulation of methotrexate in Ehrlich ascites tumor cells in vitro ' (1985 ) 34 Biochem. Pharmacol. : 747 -754.

    • Search Google Scholar
  • Takeda, M., Khamdang, S., Narikawa, S. és mtsai: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J. Pharmacol. Exp. Ther., 2002, 302, 666–671.

    Narikawa S. , 'Characterization of methotrexate transport and its drug interactions with human organic anion transporters ' (2002 ) 302 J. Pharmacol. Exp. Ther. : 666 -671.

    • Search Google Scholar
  • Sani, S. N., Henry, K., Bohlke, M. és mtsai: The effects of drug transporter inhibitors on the pharmacokinetics and tissue distribution of methotrexate in normal and tumor-bearing mice: a microdialysis study. Cancer Chemother. Pharmacol., 2010, 66, 159–169.

    Bohlke M. , 'The effects of drug transporter inhibitors on the pharmacokinetics and tissue distribution of methotrexate in normal and tumor-bearing mice: a microdialysis study ' (2010 ) 66 Cancer Chemother. Pharmacol. : 159 -169.

    • Search Google Scholar
  • Ferrazzini, G., Klein, J., Sulh, H. és mtsai: Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia. J. Pediatr., 1990, 117, 823–826.

    Sulh H. , 'Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia ' (1990 ) 117 J. Pediatr. : 823 -826.

    • Search Google Scholar
  • Yamamoto, K., Sawada, Y., Matsushita, Y. és mtsai: Delayed elimination of methotrexate associated with piperacillin administration. Ann. Pharmacother., 1997, 31, 1261–1262.

    Matsushita Y. , 'Delayed elimination of methotrexate associated with piperacillin administration ' (1997 ) 31 Ann. Pharmacother. : 1261 -1262.

    • Search Google Scholar
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 33 30 0
PDF Downloads 67 65 4