Simultaneous central nervous system distribution and pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect of norfloxacin administered at a convulsant dose in rats

The objective of this study was to investigate the contribution of norfloxacin blood-brain barrier (BBB) transport to its delayed electroencephalogram (EEG) effect in rats. Norfloxacin was injected as a bolus dose of 150 mg kg(-1). Blood samples were collected for total norfloxacin plasma concentration measurements. The corresponding unbound levels were determined in brain extracellular fluid (ECF) using microdialysis. Quantitative EEG recording was conducted during 9 h post-dose. Brain ECF norfloxacin concentrations were much lower than plasma levels (AUC ratio=9.7+/-2.8%) but peaked very early, and concentration versus time profiles were parallel in both biological fluids. The best pharmacokinetic (PK) modelling was obtained by considering that ECF concentrations were part of the central compartment, with a proportionality factor. The peak of EEG effect was delayed and the effect versus plasma concentration curves exhibited a dramatic hysteresis. A PK-pharmacodynamic (PD) effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site successfully described the data. Comparisons of PK-PD parameters estimated from plasma and ECF concentrations show that most of the delayed norfloxacin EEG effect is not due to BBB transport, but also that PD parameters derived from plasma data must be carefully interpreted when drug distribution at the effect site is restricted, as may often be the case for centrally acting drugs.     

Dermal pharmacokinetics of pyrazinamide determined by microdialysis sampling in rats

Studies have demonstrated the efficacy of pyrazinamide (PZA) against stages of the Leishmania parasite that causes cutaneous leishmaniasis. Although PZA is widely distributed in most body fluids and tissues, the amount of drug reaching the skin is unknown. This study aimed to investigate the pharmacokinetics of PZA in rat dermal tissue by dermal microdialysis. Skin pharmacokinetics was assessed by implanting a linear microdialysis probe in the dermis of ten rats. In addition, blood samples were collected to assess plasma pharmacokinetics. Unbound microdialysate (N?=?280) and plasma (N?=?120) concentrations following single intravenous doses of 25?mg/kg or 50?mg/kg PZA were quantified by a validated HPLC method. Probe calibration was performed by retrodialysis. Non-compartmental analysis and non-linear mixed-effects modelling were performed using WinNonlin and NONMEM v.7.3. PZA rapidly permeated into the dermis and reached high levels, with mean maximum concentrations (C_max) of 22.4?±?7.1?µg/mL and 48.6?±?17.3?µg/mL for the two doses studied. PZA showed significant distribution to the skin (fAUC_dermal/fAUC_plasma?=?0.82?±?0.31 and 0.84?±?0.25 for 25?mg/kg and 50?mg/kg doses, respectively). Active unbound concentrations in dermal tissue reached lower levels than free plasma concentrations, indicating that free PZA levels in plasma were in equilibrium with tissue levels. These results showed equivalent unbound drug tissue concentrations and corresponding unbound plasma levels. This study shows that PZA distributes rapidly into dermal interstitial fluid space in rats and therefore may be a potential agent in the treatment of cutaneous leishmaniasis.     

Tissue penetration of cefpodoxime into the skeletal muscle and lung in rats

PURPOSE: The aim of this study was to investigate the pharmacokinetics of cefpodoxime in interstitial tissue fluids (skeletal muscle and lung) in rats by microdialysis, and to examine the relationship between free drug levels in plasma and in tissues. METHODS: Cefpodoxime was administered to anesthetized male Wistar rats as single intravenous bolus of 10 or 20 mg/kg and constant infusion of 260 microg/h with a loading dose. The protein binding of cefpodoxime in rat plasma was determined using ultrafiltration. RESULTS: The average protein binding of cefpodoxime in rat plasma was 38%. The half-lives in plasma, muscle and lung were similar (approximately 5 h). After constant rate infusion, the free concentrations in the muscle and the lung were almost identical, but lower than total and free plasma concentrations. The data were modeled simultaneously using a two-compartmental body model. CONCLUSIONS: Free interstitial levels of cefpodoxime in muscle and lung tissue are very similar. Since muscle is more accessible than lung, free muscle concentrations may serve as a good surrogate for unbound concentrations in lung.     

Chronic dose urinary and serum pharmacokinetics of norfloxacin in the elderly.

1. Norfloxacin was administered as two daily 400 mg oral doses to eight elderly patients requiring treatment for urinary tract infections. Blood specimens were obtained for pharmacokinetic profiles following the first and fifteenth doses. Further specimens were obtained before each morning's dose of norfloxacin. Specimens of urine were obtained to ascertain if adequate antimicrobial concentrations were reached in these patients with diminished renal function. 2. Norfloxacin half-life was consistent with that expected in mild renal impairment and was not different between the first and fifteenth doses. Based on ratios of AUC values, accumulation is probably related to renal function, being greatest for creatinine clearance values below 30 ml min-1. 3. On the great majority of occasions, the urinary concentrations of norfloxacin exceeded 20 micrograms ml-1. On days 2-7, the mean percentage 12 h renal elimination of norfloxacin was 18.6 +/- 1.47 (mean of 82 separate observations). Norfloxacin 400 mg twice daily was well tolerated in this group of elderly patients and produced adequate antimicrobial concentrations in urine.     

Dose ranging pharmacokinetics and brain distribution of norfloxacin using microdialysis in rats

The purpose of this study was to investigate the effect of dose on norfloxacin pharmacokinetics and distribution into the brain extracellular fluid (ECF), in freely moving rats. Unbound concentrations of norfloxacin in hippocampus were determined by microdialysis after an i.v. bolus dose of 12.5, 25, 50, 100, or 150 mg/kg in rats. In vivo recovery of norfloxacin was determined by retrodialysis by calibrator. Among three fluoroquinolones (enoxacin, pefloxacin, and ciprofloxacin) selected as potential calibrators, ciprofloxacin was selected as the best one. Maximum ECF brain norfloxacin concentrations are rapidly obtained but the ECFbrain/plasma areas under curves (AUC) ratios are low and independent of dose with a mean value of 8.2 +/- 5.8%. By contrast, norfloxacin systemic pharmacokinetics was nonlinear, with total plasma clearance decreasing significantly from 23.0 +/- 3.4 to 14.4 +/- 3.8 mL/min/kg when dose increased from 12.5 to 150 mg/kg.     

Effect of simulated microgravity on the disposition and tissue penetration of ciprofloxacin in healthy volunteers

This study evaluated the effects of simulated microgravity (smuG) on the pharmacokinetics of ciprofloxacin. Six healthy volunteers participated in a crossover study to compare the pharmacokinetics of ciprofloxacin after a single 250-mg oral dose in normal gravity (1G) and smuG. Plasma and urine samples were collected, and in vivo microdialysis was employed to obtain the free interstitial concentrations in the thigh muscle. Tissue penetration (f) was determined as the ratio of the free tissue area under the concentration versus time curve (AUC(tiss,free))/AUC(plasma,free). Plasma and free interstitial ciprofloxacin concentrations were simultaneously fit to a 1-compartment body model after correction for protein binding and tissue penetration. Total and free plasma concentrations were very similar in smuG and 1G. Tissue penetration in smuG (f =0.61 +/- 0.36) was slightly lower than in 1G (f =0.92 +/- 0.63); however, the difference was not significant. The authors conclude that the disposition of ciprofloxacin was not affected by simulated microgravity.     

Toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals

A toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals was undertaken using nalidixic acid as a standard drug. Norfloxacin and nalidixic acid were subcutaneously administered to rats and rabbits, orally administered to dogs, and norfloxacin was orally dosed to monkeys once a day for 7 consecutive days. Of the dose levels tested, the minimum arthropathic doses of norfloxacin were 100, 25, and 50 mg/kg/day in rats, rabbits, and dogs, respectively. At these doses, the peak serum concentrations (Cmax) on Day 6 were 16.1, 9.73, and 5.11 micrograms/ml, and the areas under the serum concentration/time curve (AUC0----infinity) were 31.9, 22.9, and 26.2 micrograms.hr/ml, in respective animals. Monkeys showed no arthropathy with norfloxacin at doses of less than 500 mg/kg/day, at which the Cmax and AUC0----infinity were 15.6 micrograms/ml and 103 micrograms.hr/ml, respectively. The minimum arthropathic doses of nalidixic acid were 50, 100, and 25 mg/kg/day in rats, rabbits, and dogs, respectively. The Cmax and AUC0----infinity of nalidixic acid were higher than those of norfloxacin in all animals. Joint tissues took up more norfloxacin than nalidixic acid, but when arthropathy was present the articular cartilage concentrations of the two drugs were in the same range. The penetration of norfloxacin into the articular cartilage was the same regardless of the joint's anatomical locations, but differed among species, being highest in rats and lowest in monkeys. The Cmax and AUC0----infinity of norfloxacin in animals at their arthropathic doses were far higher than those measured clinically in children, whereas those of nalidixic acid in animals did not differ much from its clinical parameters.     

Microdialysis of triamcinolone acetonide in rat muscle

The objective of this study was to compare plasma and muscle concentrations of triamcinolone acetonide (TA) in the rat by microdialysis. Microdialysis experiments were carried out at steady state in rats after an initial I.V. bolus 50 mg/kg of the phosphate ester of TA (TAP) followed by 23 mg/kg/h infusion. In vivo recovery was calculated by retrodialysis. The concentration determined at steady state in microdialysate, corrected for recovery, was 2.73 +/- 0.42 microg/mL compared to 21.9 +/- 2.3 microg/mL in plasma. The pharmacokinetics of TA in plasma was described by an open two-compartment model with a terminal half-life of 2.7 h. The clearance of TA in rats determined by compartmental analysis was 0.94 L/h/kg. The measured microdialysate levels of TA in muscle, corrected for recovery, were comparable to the predicted free drug levels in the peripheral compartment. Protein binding in rat plasma, measured by ultrafiltration, was 90.1%. The microdialysis in vivo recovery in muscle was similar to the in vitro recovery under stirred conditions. The results show the applicability of microdialysis to measure free tissue concentrations of TA in rats.     

Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs

Inadequate tissue penetration of antibiotics can lead to therapeutic failure and bacterial resistance. Pharmacokinetic evaluation of antibiotics should therefore be based on tissue rather than serum concentrations. Over several years, tissue concentration data obtained by methods such as tissue biopsies have flawed the correct interpretation of antibiotic tissue distribution. Microdialysis--a semi-invasive catheter-based sampling technique--has been employed for the in vivo measurement of antibiotic tissue pharmacokinetics. Owing to selective access to the target site for most anti-infective drugs, microdialysis satisfies regulatory requirements for pharmacokinetic distribution studies and might become a reference technique for tissue distribution studies in the near future. Furthermore, microdialysis might contribute to the definition of meaningful surrogate markers for antibiotic efficiency during drug development.     

Tissue penetration of cefpodoxime and cefixime in healthy subjects

Microdialysis is a technique that allows the measurement of free antibiotic concentrations in different tissues, which are responsible for the antibacterial activity at the infection site. In an open, randomized, 2-way crossover study in healthy volunteers, the muscle penetration of orally administered cefpodoxime (400 mg) and cefixime (400 mg) was compared using microdialysis. The results show that the total plasma concentration-time profiles of each antibiotic were similar; the area under the curve for cefpodoxime was 22.4 +/- 8.7 versus 25.6 +/- 8.5 mg/L*h for cefixime. However, tissue penetration was twice as high for cefpodoxime (area under the curve 15.4 +/- 5.1 mg/L*h) as for cefixime (area under the curve 7.3 mg/L*h). This degree of tissue distribution is consistent with their protein binding of 21% for cefpodoxime and 65% for cefixime. After equilibration, the unbound tissue concentrations of both antibiotics were similar to their unbound plasma concentrations. Pharmacokinetic modeling was applied to describe the pharmacokinetic profiles in plasma and muscle. The study demonstrates that cefpodoxime shows greater tissue penetration than cefixime.     

Tissue pharmacokinetics of levofloxacin in human soft tissue infections

AIMS: The present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection. METHODS: Tissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high-performance liquid chromatography. RESULTS: The mean concentration vs time profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentration vs time curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 +/- 1.0 for inflamed and 1.1 +/- 0.6 for healthy subcutaneous adipose tissue (mean +/- SD). The mean difference in the ratio of the AUC(tissue) : AUC(plasma) for inflamed and healthy tissue was 0.09 (95% confidence interval -0.58, 0.759, P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUC(tissue) : AUC(plasma) ratios. CONCLUSIONS: The penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub-therapeutic.     

In-vivo Microdialysis Study of the Distribution of Cisplatin into Brain Tumour Tissue after Intracarotid Infusion in Rats With 9L Malignant Glioma

Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats. Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg^?) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%. It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.     

Penetration of Cefaclor Into the Interstitial Space Fluid of Skeletal Muscle and Lung Tissue in Rats

Purpose. To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model. Methods. Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v. bolus doses of 50 and 75 mg/kg cefaclor. Unbound muscle concentrations were also measured after a primed, continuous i.v. infusion at an infusion rate of 0.3 mg/kg/min. Results. The cefaclor half-life in plasma, muscle and lung was approximately 1 h. Unbound cefaclor concentrations in muscle and lung were found to be virtually identical. A 2-compartment body model was fitted to the data with a tissue penetration factor (AUC_{tissue(unbound)}/AUC_{plasma(unbound)}) of approximately 0.26 independent of dose, tissue and mode of administration. Conclusions. Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma. Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy. Instead, therapeutically active levels of cefaclor at the site of action should be taken into account. Microdialysis allows direct measurement of these unbound concentrations.     

Quantification and prediction of skin pharmacokinetics of amoxicillin and cefuroxime

The purpose of this project was to develop and validate a pharmacokinetic model and to quantify the rate and extent of distribution between plasma and skin of two β‐lactam antibiotics, amoxicillin (AMX) and cefuroxime (CFX), which are frequently administered systemically to treat skin and skin structure infections. Dosing regimens are usually based on plasma concentration, however, concentrations at the target site are better correlated with the effect. For each antibiotic, three different i.v. bolus doses were administered to three female rabbits according to a randomized cross‐over design and plasma samples were collected serially. Skin concentrations were obtained by continuous microdialysis. Skin and unbound plasma concentrations were fitted simultaneously using a semi‐physiological model and the transfer constants plasma/skin (K_in) and skin/plasma (K_out) were estimated. K_in and K_out were then used to predict skin concentrations from the plasma levels obtained from an oral administration of AMX or from an i.v. bolus of CFX. The predicted skin profiles were similar to those measured by microdialysis during the actual experiments. In conclusion, this study shows that it is possible to generate a reasonable prediction of skin pharmacokinetics from any plasma level once a careful characterization of the transfer process between plasma and skin has been made. Copyright © 2009 John Wiley & Sons, Ltd.     

Microdialysis for pharmacokinetic analysis of drug transport to the brain

The intracerebral microdialysis technique represents an important tool for monitoring free drug concentrations in brain extracellular fluid (brain(EcF)) as a function of time. With knowledge of associated free plasma concentrations, it provides information on blood-brain barrier (BBB) drug transport. However, as the implantation of the microdialysis probe evokes tissue reactions, it should be established if the BBB characteristics are maintained under particular microdialysis experimental conditions. Several studies have been performed to evaluate the use of intracerebral microdialysis as a technique to measure drug transport across the BBB and to measure regional pharmacokinetics of drugs in the brain. Under carefully controlled conditions, the intracerebral microdialysis data did reflect passive BBB transport under normal conditions, as well as changes induced by hyperosmolar opening or by the presence of a tumor in the brain. Studies on active BBB transport by the mdr1a-encoded P-glycoprotein (Pgp) were performed, comparing mdr1a(-/-) with wild-type mice. Microdialysis surgery and experimental procedures did not affect Pgp functionality, but the latter did influence in vivo concentration recovery, which was in line with theoretical predictions. It is concluded that intracerebral microdialysis provides meaningful data on drug transport to the brain, only if appropriate methods are applied to determine in vivo concentration recovery.     

Pharmacokinetics and tissue distribution of olanzapine in rats

The single dose pharmacokinetics of olanzapine in rats, following an oral dose and its distribution in the brain and other tissues after repeated oral and intra-peritoneal (i.p.) administration, were studied. Olanzapine in plasma, brain, liver, lung, kidney, spleen and fat was assayed at predose, 0.25, 0.5, 1, 2, 5, 12, 24, 36, 48 h postoral dose of 6 mg/kg and after daily oral and i.p. doses of 0.25, 1, 3, and 6 mg/kg/day of olanzapine for 15 consecutive days by a sensitive and specific HPLC method with electrochemical detection. Olanzapine was readily absorbed and distributed in plasma and tissues as the peak concentrations were reached within approximately 45 min after the oral dose. The terminal half-life of olanzapine in plasma was 2.5 h and in tissues it ranged from 3 to 5.2 h. The area under the concentration-time curve (AUC(last)) was lowest in plasma and largest in liver and lung. The AUC(last) of olanzapine was eight times larger in brain and three to 32 times larger in other tissues than that in plasma. After repeated oral doses, the plasma and tissue concentrations of olanzapine were generally higher than those after repeated i.p. doses. The liver and spleen had the highest concentrations after oral and i.p doses, respectively. In both cases, the tissue concentrations were four- to 46-fold higher than that in plasma and correlated with administered doses. Likewise, plasma concentrations strongly correlated with the simultaneous brain and tissue concentrations (r(2)>0.908, p<0.0001). On average, the brain levels were 6.3-13.1 and 5.4-17.6 times higher than the corresponding plasma level after oral and i.p. doses, respectively. The tissue to plasma level ratio of olanzapine was higher in other tissues. The data indicated that olanzapine is rapidly absorbed and widely distributed in the tissues of rats after oral and i.p. administration. The plasma concentration appears to predict the simultaneous concentration in brain and other tissues. There was no marked localized accumulation of olanzapine in any of the regions of the rat brain.     

Norfloxacin does not alter warfarin's disposition or anticoagulant effect

Drug interactions related to inhibition of hepatic drug metabolism have been identified for some fluoroquinolone antibiotics. This study was designed to investigate whether the fluoroquinolone norfloxacin at the usual clinical dosage interacts with the anticoagulant agent warfarin. Ten healthy male subjects were administered a single oral dose of 30 mg warfarin sodium alone or during multiple-dose treatment with norfloxacin, 400 mg bid, in a randomized, crossover fashion. Plasma warfarin concentrations and prothrombin times were measured for 6 days after each of the two warfarin doses. The pharmacokinetic parameters of warfarin were comparable in the absence and presence of norfloxacin, including no significant differences in warfarin's elimination half-life, apparent total clearance, apparent volume of distribution, or peak plasma concentration. Norfloxacin also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction observed in this study suggests that a clinically important interaction of norfloxacin and warfarin is unlikely to occur in patients requiring both drugs.     

Pharmacokinetics and dose proportionality of BMS-204352 after intraarterial administration to rats

BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the dose proportionality and pharmacokinetics of BMS-204352 in rats. In an open, parallel fashion, sixteen rats per gender received a single intraarterial dose of BMS-204352 as a 3-min infusion into the carotid artery at 0.4, 2.0, 5.0 and 10.0 mg/kg dose levels. Serial blood samples were collected for up to 24 h post-dose and plasma samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic mass spectrometric (LC/MS) method. Pharmacokinetic analysis was performed using a non-compartmental method. Results revealed a gender difference in the pharmacokinetics of BMS-204352 in rats at all doses excluding the first (i.e., 0.4 mg/kg) dose panel. BMS-204352 peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) values increased in a proportion greater than the increment in dose. Specifically, as dose increased in the ratio 1:5:12.5:25, C(max) increased in the ratio 1:7:18:31 in male rats and 1:7:22:51 in female rats. The respective AUC ratios were 1:6:20:42 in male rats and 1:12:29:77 in female rats. Mean total body clearance (CL(T)) values for BMS-204352 ranged from 879-3242 ml/h/kg over the four dose levels and generally decreased with increase in dose. Similarly, steady state volume of distribution (V(SS)) values ranged from 3621-8933 ml/kg over the four dose levels and generally decreased with increase in dose. However, mean residence time (MRT) and elimination half-life (T(1/2)) values for BMS-204352 were independent of dose and ranged from 2.42-4.54 to 2.08-4.70 h, respectively. In conclusion, BMS-204352 appears to exhibit dose-dependent pharmacokinetics in rats. In addition, there appeared to be some evidence of gender related differences in the pharmacokinetics of BMS-204352.     

Quantitation of norfloxacin, a new antibacterial agent in human plasma and urine by ion-pair reverse-phase chromatography

A specific and sensitive high-performance liquid chromatographic method for the analysis of norfloxacin in human plasma and urine is described. Norfloxacin was extracted from the sample matrix using dichloromethane under neutral conditions, followed by back extraction into dilute phosphoric acid for chromatographic analysis on a reverse-phase column with a mobile phase consisting of methanol, phosphate buffer, and ion-pairing reagent (pH 3.0) at a flow rate of 2.0 mL/min. The ability of this method to distinguish intact norfloxacin from its metabolites was demonstrated. The method is linear, quantitative, and reproducible for both plasma analysis (0.05-2.5 microgram/mL) and urinalysis (1.0-500 micrograms/mL) using peak area ratios (norfloxacin-internal standard) for quantitation. The stability of norfloxacin and its metabolites in dilute phosphoric acid was studied. To assess the presence of norfloxacin conjugates in the urine of dosed individuals, the effects of urine hydrolysis on drug quantitation were examined. Urine and plasma levels of norfloxacin at selected time points following the administration of single drug doses are presented.     

Evaluation of gatifloxacin penetration into skeletal muscle and lung by microdialysis in rats

This study aimed to investigate gatifloxacin distribution into skeletal muscle and lung interstitial fluid by microdialysis and to correlate free tissue and free plasma levels of the drug. Microdialysis recoveries were determined in vitro by extraction efficiency and retrodialysis at 80, 160 and 400 ng/ml resulting in 33.5+/-1.3%, 33.1+/-1.2%, 31.8+/-2.7% and 31.4+/-2.6%, 33.1+/-2.2%, 30.6+/-3.3%, respectively. In vivo recovery by retrodialysis in Wistar rats' skeletal muscle and lung were 29.1+/-1.0% and 30.7+/-1.4%, respectively. The recovery was constant and independent on the method or media used. Gatifloxacin tissue penetration was investigated after intravenous dosing of 6 mg/kg to Wistar rats. Free skeletal muscle, lung and plasma profiles were virtually superimposable resulting in similar area under the curve (AUC(0-9)) of 3888+/-734 ng h/ml, 4138+/-1071 ng h/ml and 3805+/-577 ng h/ml, respectively (alpha=0.05). The tissue distribution factors were 1.02 and 1.08 for muscle and lung relative to plasma. In conclusion, free plasma levels are a good surrogate for gatifloxacin active levels at the infection site.