TY - JOUR
T1 - Methotrexate disposition following disruption of the blood-brain barrier
AU - Susan, Markowsky J.
AU - Zimmerman, Cheryl L.
AU - Tholl, Debra
AU - Soria, Inmaculada
AU - Castillo, Reynaldo
PY - 1991/1
Y1 - 1991/1
N2 - Intracarotid drug administration after osmotic blood-brain barrier disruption (BBBD) enhances drug delivery to brain tumors. Despite clinical use, the pharmacokinetics of drugs following BBBD has not been described to date. Since methotrexate exhibits a concentration-toxicity response relationship, methotrexate disposition was determined following BBBD and intracarotid administration in seven patients with nonoperable brain tumors. Following a 1.5–5 g intracarotid methotrexate injection, 12 blood samples and 9 urine collections were obtained. Methotrexate concentrations in serum and urine were determined by fluorescence polarization immunoassay. The serum concentration-time data were best described by a three-compartment model. Systemic and renal clearances were consistent with previous studies. However, a prolonged mean terminal half-life of 51.5 h was observed. Serum methotrexate concentrations at 72 h exceeded 0.1 mol/L in five of seven patients. Stomatitis occurred in one patient. Relative to previous reports, prolonged methotrexate half-life and cytotoxic methotrexate concentrations were observed in the serum of patients receiving intracarotid methotrexate following BBBD. Due to the prolonged cytotoxic methotrexate concentrations observed, extended leucovorin therapy may be indicated following BBBD and intracarotid methotrexate.
AB - Intracarotid drug administration after osmotic blood-brain barrier disruption (BBBD) enhances drug delivery to brain tumors. Despite clinical use, the pharmacokinetics of drugs following BBBD has not been described to date. Since methotrexate exhibits a concentration-toxicity response relationship, methotrexate disposition was determined following BBBD and intracarotid administration in seven patients with nonoperable brain tumors. Following a 1.5–5 g intracarotid methotrexate injection, 12 blood samples and 9 urine collections were obtained. Methotrexate concentrations in serum and urine were determined by fluorescence polarization immunoassay. The serum concentration-time data were best described by a three-compartment model. Systemic and renal clearances were consistent with previous studies. However, a prolonged mean terminal half-life of 51.5 h was observed. Serum methotrexate concentrations at 72 h exceeded 0.1 mol/L in five of seven patients. Stomatitis occurred in one patient. Relative to previous reports, prolonged methotrexate half-life and cytotoxic methotrexate concentrations were observed in the serum of patients receiving intracarotid methotrexate following BBBD. Due to the prolonged cytotoxic methotrexate concentrations observed, extended leucovorin therapy may be indicated following BBBD and intracarotid methotrexate.
KW - Blood-brain barrier disruption
KW - Brain tumor
KW - Methotrexate pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=0026100744&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026100744&partnerID=8YFLogxK
U2 - 10.1097/00007691-199101000-00002
DO - 10.1097/00007691-199101000-00002
M3 - Article
C2 - 2057988
AN - SCOPUS:0026100744
SN - 0163-4356
VL - 13
SP - 24
EP - 31
JO - Therapeutic drug monitoring
JF - Therapeutic drug monitoring
IS - 1
ER -