CRITICAL KETOCONAZOLE DOSAGE RANGE FOR CICLOSPORIN CLEARANCE INHIBITION IN THE DOG

被引:34
作者
MYRE, SA [1 ]
SCHOEDER, TJ [1 ]
GRUND, VR [1 ]
WANDSTRAT, TL [1 ]
NICELY, PG [1 ]
PESCE, AJ [1 ]
FIRST, MR [1 ]
机构
[1] UNIV CINCINNATI,MED CTR,COLL MED,CINCINNATI,OH 45267
关键词
CICLOSPORIN CLEARANCE; KETOCONAZOLE; DRUG INTERACTION; DOSE REQUIREMENTS;
D O I
10.1159/000138850
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p > 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not signiicantly greater than the 85% reduction occurring agter only 10 mg/kg/day KC (p > 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p < 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p > 0.05). We conclude from these new observations that the KC-induced decrease in CsA Cl(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5-10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.
引用
收藏
页码:233 / 241
页数:9
相关论文
共 31 条
[1]   PHARMACODYNAMICS OF CYCLOSPORINE-KETOCONAZOLE INTERACTION IN MICE - COMBINED THERAPY POTENTIATES CYCLOSPORINE IMMUNOSUPPRESSION AND TOXICITY [J].
ANDERSON, JE ;
MORRIS, RE ;
BLASCHKE, TF .
TRANSPLANTATION, 1987, 43 (04) :529-533
[2]   EFFECT OF KETOCONAZOLE ON HEPATIC OXIDATIVE DRUG-METABOLISM [J].
BROWN, MW ;
MALDONADO, AL ;
MEREDITH, CG ;
SPEEG, KV .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1985, 37 (03) :290-297
[3]  
BRUNING J, 1977, COMPUTATIONAL HDB ST, P19
[4]   CYCLOSPORINE DISPOSITION IN THE DOG - COMPARISON OF RADIOIMMUNOASSAY WITH HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY AND PHARMACOKINETICS FOLLOWING INTRAVENOUS ADMINISTRATION [J].
BUICE, RG ;
GURLEY, BJ ;
STENTZ, FB ;
SIDHU, P ;
MCCLELLAN, T ;
WILLIAMS, JW .
TRANSPLANTATION, 1985, 40 (05) :483-488
[5]  
CALNE RY, 1987, LANCET, V2, P506
[6]  
CARRUTHERS SG, 1983, CLIN CHEM, V29, P180
[7]  
DMELLO A, 1989, RES COMMUN CHEM PATH, V64, P441
[8]  
EVANS RW, 1988, TRANSPL P, V20, P49
[9]  
FERGUSON RM, 1982, LANCET, V2, P882
[10]  
FIRST MR, 1989, LANCET, V2, P1198, DOI 10.1016/S0140-6736(89)91802-3