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Non‐linear pharmacokinetics of ofloxacin after a single intravenous bolus dose in pigs
Author(s) -
Son D.S.,
Ikenoue N.,
Tagawa Y.,
Shimoda M.,
Kokue E.
Publication year - 2000
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1046/j.1365-2885.2000.00289.x
Subject(s) - ofloxacin , pharmacokinetics , intravenous bolus , medicine , bolus (digestion) , pharmacology , anesthesia , chemistry , antibiotics , ciprofloxacin , biochemistry
The pharmacokinetics of ofloxacin (OFLX) was investigated after intravenous administration of 3, 10 and 30 mg/kg of body weight in pigs. Plasma OFLX concentration–time course collected from the highest dosage showed a convex decline, indicating a capacity‐limited process in drug elimination (Michaelis–Menten elimination). Dose–normalized area under curve ( AUC / Dose ) and mean resident time ( MRT ) were dose‐dependent, indicating a classical pattern of non‐linear elimination pharmacokinetics. Based on simultaneous curve fitting from three doses, non‐linear pharmacokinetic parameters were as follows: 0.87 mg/h/kg for maximum velocity, 2.20 μg/mL in Michaelis–Menten constant and 2.06 L/kg for apparent volume of distribution. Based on a model‐independent analysis, the apparent volume of distribution at steady‐state ( V dss) was dose‐independent whereas total body clearance ( CL tot) was dose‐dependent, mainly contributed by renal clearance ( CL r) with the regression line of CL tot=1.14× CL r+0.09 ( r =0.92). The intercept of the regression line indicates non‐renal clearance ( CL nr), corresponding to the value of observed CL nr without dose‐dependency. Because of a higher CL r compared with glomerular filtration rate ( GFR ) in spite of drug reabsorption, the CL r must contain the renal active tubular secretion. With increasing dosage, the level of saturation of tubular secretion of OFLX decreased the CL r, resulting in the decrease in CL tot. The plasma protein binding to OFLX was dose‐independent: mean free fraction ( fp )=0.73, with probably no influential effect on OFLX disposition. In conclusion, the degree of saturation in the renal active tubular secretion of OFLX could be a major causal factor in the alteration of CL r in an increasing dosage of OFLX. Accordingly, the alteration of CL r could directly induce the non‐linear pharmacokinetics of OFLX in pigs, an important consideration in clinical therapeutics.