Davis J D, Aarons L, Houston J B
Pharmacy Department, University of Manchester, England.
Pharm Res. 1994 Oct;11(10):1424-8. doi: 10.1023/a:1018991822440.
Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33-46) at steady state plasma concentrations of 0-33 mg.l-1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg.kg-1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 microM and 16.3 microM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were 'designed out.'
某些氟喹诺酮类抗生素通过抑制茶碱（THEO）的代谢来影响其处置，但迄今为止尚无研究调查氟喹诺酮类血浆浓度与THEO药代动力学之间的关系。在雄性斯普拉格-道利大鼠（n = 33 - 46）中研究了两种氟喹诺酮类药物依诺沙星（ENOX）和环丙沙星（CIPRO）的作用，通过静脉推注剂量并持续输注使血浆浓度达到0 - 33 mg·l-1的稳态。使用竞争抑制模型描述了稳态ENOX和CIPRO血浆浓度对静脉注射6 mg·kg-1剂量后测定的THEO清除率的影响。该模型由两个部分组成，一个描述不受氟喹诺酮影响的THEO清除率的残余部分，另一个描述氟喹诺酮对THEO清除率的非线性降低。从模型估计的残余清除率与大鼠中THEO的肾清除率相当。每种氟喹诺酮的效力通过Ki值来表征，该浓度可使THEO清除率降低最大变化的50%。ENOX和CIPRO的这些值分别为4.7 microM和16.3 microM。因此，在本研究中，发现ENOX比CIPRO是更有效的THEO清除率抑制剂。该方法允许直接在体内比较不同氟喹诺酮类药物的效力，因为药代动力学差异，如清除率、分布容积和生物利用度等都被“设计排除”了。
