Pharmacokinetic Modeling of Free Amoxicillin Concentrations in Rat Muscle Extracellular Fluids Determined by Microdialysis

Abstract

The aim of the present study was to investigate amoxicillin (AMX) distribution in muscle interstitial fluid by microdialysis in healthy, awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Probe recoveries in each rat were determined by retrodialysis with cefadroxil. AMX was administered as a bolus dose of 50 mg · kg ؊1 , and microdialysis samples were collected during 180 min. Concentrations of unbound drug in blood and muscle were analyzed simultaneously by a population approach. Simulations were conducted using a hybrid, physiologically based pharmacokinetic model to investigate the potential impact of tissue blood flow on muscle AMX distribution. A two-compartment pharmacokinetic model described adequately the unbound amoxicillin concentration-time profiles in blood and muscle. Muscle AMX distribution equilibrium was rapidly achieved. Consequently, the best results were obtained by considering concentrations in muscle as part of the central compartment. The ratio of the concentration of unbound drug in muscle to that in blood (R model ) was estimated to 0.80 by the model, which is close to the mean value obtained by noncompartmental data analysis (R area ‫؍‬ 0.86 ؎ 0.29). Simulations conducted with a hybrid, physiologically based pharmacokinetic model suggest that a muscle blood flow reduction of 30% to 50%, such as could be encountered in critical care patients, has virtually no effect on muscle AMX concentration profiles. In conclusion, this study has clearly demonstrated that AMX distributes rapidly and extensively within muscle interstitial fluid, consistent with theory, and that altered muscle blood flow seems unlikely to have a major effect on these distribution characteristics.

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

“…In fact, this has been confirmed experimentally on many occasions, in particular, during experimental microdialysis studies conducted by several groups with rats and various antibiotics, including piperacillin (4, 26); ceftriaxone (18); pazufloxacin, ciprofloxacin, ofloxacin, and ceftazidime (1); imipenem (24); and amoxicillin (25). For similar reasons, ECF concentrations should be identical in various soft tissues, which in fact constitutes the rationale for conducting microdialysis studies with muscle tissue, which is more easily accessible, although possibly less relevant, than lung tissue.…”

“…Then, the time to the peak concentration in soft tissues may potentially be delayed during hypovolemia. However, the monoexponetial decay of blood IPM concentrations with time, together with the rapid peak occurrence in muscle and lung tissues (24), suggests that this distribution is virtually instantaneous and is unlikely to be noticeably delayed by reduced blood flow, as has recently been documented with amoxicillin (25).…”

“…Experiments with animals allow better control of these multiple interfering parameters, and many microdialysis studies have also been conducted with rats to investigate the distribution of amino ␤-lactams in muscle (4,7,18,20,21,22,24,25). Muscle tissue has frequently been chosen because it is relatively accessible and the concentrations in muscle tissue seem to be a reasonable predictor of the unbound concentrations in more therapeutically relevant tissues, such as lung tissue (7,20,21).…”

Quantification and prediction of skin pharmacokinetics of amoxicillin and cefuroxime

“…Microdialysis was used to study the pharmacokinetics of AMX in muscle interstitial fluid of rats [27] and in middle ear of chinchilla [28], while in the case of CFX microdialysis was applied to study the pharmacokinetics in the skeletal muscle of humans during cardiac surgery [29] and in the rat brain [12]. This is the first time microdialysis has been applied to study the dermal pharmacokinetics of AMX and CFX in rabbits.…”

Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats

“…To date, several approaches have been proposed to overcome these difficulties, and among them, an approach using the microdialysis method seems to be the most suitable to evaluate the intramuscular drug concentration in vivo (Araki et al, 2002;Marchand et al, 2005). In this approach, a tiny probe equipped with a semi-permeable membrane is precisely embedded in muscle.…”