Effect of ofloxacin on theophylline pharmacokinetics at clinical dosage in dogs

Abstract

We examined the effects of ofloxacin (OFX) and norfloxacin (NFX) on theophylline (TP) pharmacokinetics in dogs. OFX, as a noncompetitive and mechanism-based inhibitor, and NFX, as a noncompetitive inhibitor, were orally administered (5 mg/kg) for a single dose or multiple doses (12 hourly for 3 days). TP (5 mg/kg, i.v) was injected at 2 h after the final dose of the fluoroquinolones (FQs). The same dose of TP was injected (i.v) 3 weeks before the start of FQs treatment for control. Multiple doses of OFX significantly reduced the total body clearance (Cl(B)) of TP from 0.117 to 0.085 L/h/kg, although a single dose did not change it. Neither a single dose nor multiple doses of NFX changed the TP pharmacokinetics. Plasma NFX concentrations increased after multiple doses. Those of OFX also increased but were still two orders of magnitude below the K(i) for noncompetitive inhibition of CYP1A in dogs. Time-dependent reduction in Cl(B) of TP suggests that mechanism-based inhibition of OFX was the major mode to decrease Cl(B) of TP. The mechanism-based inhibition may result in substantial inhibition of CYP1A activities in clinical conditions.

Lack of inhibitory effects of several fluoroquinolones on cytochrome P‐450 3A activities at clinical dosage in dogs

“…FQs, therefore, can be used in a co‐administration therapy with CYP3A substrates without the risk of adverse drug interaction in clinical conditions in dogs. However, much attention must be paid when FQs are co‐administered with CYP1A substrates because the drugs inhibit CYP1A activities and may result in drug–drug interaction in dogs (Regmi et al. , 2006).…”

“…These reversible and mechanism‐based inhibitory effects of FQs on CYP3A may be of clinical importance if the effects are substantial at clinical doses. Reversible noncompetitive and mechanism‐based inhibitory effects of ofloxacin (OFX) on CYP1A activities significantly prolonged the elimination of theophylline at therapeutic dosage in dogs (Regmi et al. , 2006).…”

“…These reversible and mechanism-based inhibitory effects of FQs on CYP3A may be of clinical importance if the effects are substantial at clinical doses. Reversible noncompetitive and mechanism-based inhibitory effects of ofloxacin (OFX) on CYP1A activities significantly prolonged the elimination of theophylline at therapeutic dosage in dogs (Regmi et al, 2006). Intorre et al (1995) observed progressive increment of plasma theophylline concentrations at steady state after each intravenous dosing of EFX at a therapeutic dosage in dogs.…”

Inhibitory Effects of Several Fluoroquinolones on Feline CYP1A and 3A in Hepatic Microsomes

“…However, the K i values for several FQs on CYP1A showed smaller values for NFX (1/40), OBFX (1/26), EFX (1/7), and OFX (1/8) compared to those of dogs [13]. In the case of CPFX, the K i value was almost similar to that of dogs [28]. These observations may suggest that the inhibitory effect of FQs on CYP1A activity was stronger in cats compared to that of dogs.…”

Possible drug–drug interaction in dogs and cats resulted from alteration in drug metabolism: A mini review

“…Enrofloxacin itself does not have this type of inhibitory mode and reversible inhibition is quite small [53] . Although ofloxacin shows the mode of mechanism based inhibition, it does not affect theophylline pharmacokinetics in dogs [61] . Furthermore, levofloxacin does not affect theophylline pharmacokinetics in humans [62] , although some fluoroquinolones would affect.…”