TY - JOUR
T1 - Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts
AU - Horton, Julie K.
AU - Thimmaiah, Kuntebommanahalli N.
AU - Houghton, Janet A.
AU - Horowitz, Marc E.
AU - Houghton, peter J.
N1 - Funding Information:
* Supported in part by PHS awards CA38933, CA23099 and GE-423 from the American Cancer Society and by American Lebanese Syrian Associated Charities (ALSAC). {(C orrespondence: Peter J. Houghton, Ph.D., Department of 3iochem~c~ and Clinical P~armacoiogy, St. Jude Children’s Research Hospital, 332 North Lauderdale, P.0. Box 318, Memphis, TN 38101. 1 Abbreviations: MDR, multiple drug resistance; MTD, maximal tolerated dose; VCR, vinrristine; VRP, verapamil; DOX, doxorubicin; and DMDP, N-(3,4-dimethoxyphenethyl)-N-methyl 2-(2-napthyl-M-dithane)-2-propylamine.
PY - 1989/6/1
Y1 - 1989/6/1
N2 - The effect of the calcium channel blocker verapamil (VRP) on the accumulation and retention of vincristine (VCR) has been examined in mice bearing xenografts of human rhabdomyosarcomas. The tumors were Rh18, moderately sensitive to VCR, and its subline, Rh18/VCR3, selected in vivo for primary resistance to VCR. Administration of VRP by i.p. bolus at dose levels above 75 mg/kg was limited by acute lethality. At this dose, the maximal concentration in plasma was 24 μM, with rapid elimination such that plasma concentrations reported to modulate resistance in vitro (approximately 5-10 μM) were maintained for less than 60 min. To sustain a 10 μM plasma concentration, mice were infused with VRP at 6.25 mg/kg/hr (150 mg/kg/day) for up to 7 days using osmotic pumps implanted in the peritoneal cavity. Steady-state plasma levels were ≥ 10,μM for at least 96 hr, and this schedule demonstrated minimal toxicity. Administration of VCR 20 hr after the start of VRP infusion produced significant lethality, requiring an 8-fold reduction in the VCR dose. Pharmacokinetic studies showed that VRP markedly increased the uptake and retention of VCR in small intestine, liver and kidney of mice. In small intestine, 8-fold greater levels of VCR were determined 24 hr after VCR administration, and this was associated with an increase in T 1 2 for elimination from 350 to 913 min. HPLC analysis of extracts from small intestine showed that > 90% of the radiolabel eluted with VCR or 4-desacetyl-VCR. Modulation of VCR retention was also related to the dose of VCR administered. The VRP-sensitive efflux pathway appeared more effective in certain tissues only at higher concentrations of VCR. In contrast, VRP did not alter significantly the uptake and retention of VCR in either the parent or VCR-resistant human xenografts. The data demonstrated that, in the mouse, VRP modulates the uptake and retention of VCR in several tissues, and this may indicate that drug efflux mediated by a VRP-sensitive mechanism (e.g. GP-170, associated with the multiple drug resistance phenotype) has a protective function against xenobiotics in these tissues.
AB - The effect of the calcium channel blocker verapamil (VRP) on the accumulation and retention of vincristine (VCR) has been examined in mice bearing xenografts of human rhabdomyosarcomas. The tumors were Rh18, moderately sensitive to VCR, and its subline, Rh18/VCR3, selected in vivo for primary resistance to VCR. Administration of VRP by i.p. bolus at dose levels above 75 mg/kg was limited by acute lethality. At this dose, the maximal concentration in plasma was 24 μM, with rapid elimination such that plasma concentrations reported to modulate resistance in vitro (approximately 5-10 μM) were maintained for less than 60 min. To sustain a 10 μM plasma concentration, mice were infused with VRP at 6.25 mg/kg/hr (150 mg/kg/day) for up to 7 days using osmotic pumps implanted in the peritoneal cavity. Steady-state plasma levels were ≥ 10,μM for at least 96 hr, and this schedule demonstrated minimal toxicity. Administration of VCR 20 hr after the start of VRP infusion produced significant lethality, requiring an 8-fold reduction in the VCR dose. Pharmacokinetic studies showed that VRP markedly increased the uptake and retention of VCR in small intestine, liver and kidney of mice. In small intestine, 8-fold greater levels of VCR were determined 24 hr after VCR administration, and this was associated with an increase in T 1 2 for elimination from 350 to 913 min. HPLC analysis of extracts from small intestine showed that > 90% of the radiolabel eluted with VCR or 4-desacetyl-VCR. Modulation of VCR retention was also related to the dose of VCR administered. The VRP-sensitive efflux pathway appeared more effective in certain tissues only at higher concentrations of VCR. In contrast, VRP did not alter significantly the uptake and retention of VCR in either the parent or VCR-resistant human xenografts. The data demonstrated that, in the mouse, VRP modulates the uptake and retention of VCR in several tissues, and this may indicate that drug efflux mediated by a VRP-sensitive mechanism (e.g. GP-170, associated with the multiple drug resistance phenotype) has a protective function against xenobiotics in these tissues.
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U2 - 10.1016/0006-2952(89)90405-X
DO - 10.1016/0006-2952(89)90405-X
M3 - Article
C2 - 2735930
AN - SCOPUS:0024339994
SN - 0006-2952
VL - 38
SP - 1727
EP - 1736
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -