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Antimicrobial Agents and Chemotherapy, December 2005, p. 4974-4979, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4974-4979.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Sandrine Marchand,1,2 Claire Dahyot,3 Isabelle Lamarche,1 Elodie Plan,1 Olivier Mimoz,1,3 and William Couet1,2*

EA 3809, Faculté de Médecine et de Pharmacie, BP 199, 34 rue du Jardin des Plantes, 86005 Poitiers Cedex, France,1 Laboratoire de Pharmacocinétique, PBS, CHU La Milétrie, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France,2 Département d'Anesthésie et Réanimation Chirurgicale, CHU La Milétrie, 86021 Poitiers, France3

Received 5 July 2005/ Returned for modification 22 August 2005/ Accepted 1 September 2005


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg–1 over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n = 8) and control (n = 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P < 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Nosocomial infections are of primary concern in critical care departments; and because hospitalized patients suffer from major physiological alterations with potential consequences on drug pharmacokinetics, selection of the appropriate antibiotic dosing regimens appears to be very challenging (28). Because infections occur in tissues, measurement of free antibiotic concentrations in the interstitial fluid of tissues should be the most relevant for prediction of therapeutic efficacy, at least for extracellular pathogens. Microdialysis is an elegant technique that allows such determinations (6) and that has been used to demonstrate that the tissue distributions of several antibiotics, including piperacillin (2, 15), cefpirome (16), meropenem (32), and imipenem (IPM) (31), were impaired in critical care patients. However, not only the disease state itself but also iatrogenic procedures, such as surgery or intensive care treatment, might influence drug kinetics (2, 17); and therefore, the reasons for the altered distribution are not clear. Yet, it was hypothesized that reduced tissue perfusion contributes to the reduced IPM distribution (31).

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 ß-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). A microdialysis study conducted by our group with healthy rats has recently shown that free IPM concentrations in muscle tissue, lung tissue, and blood are virtually identical at any time postdosing (24).

The objective of the present study was therefore to investigate the effect of hypovolemia on the pharmacokinetics of IPM in an experimental rat model, with special focus on its distribution, as assessed by determination of the usual pharmacokinetic parameters derived from blood concentration measurements and by comparison of the blood and muscle concentrations determined by microdialysis.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals. IPM monohydrate-sodium cilastatin salt (Tienam; Merck Sharp & Dohme-Chibret Laboratories, Paris, France) was used to prepare IPM solutions in 0.9% NaCl and Ringer solution for intravenous administration and probe perfusion, respectively. All chemicals used were of analytical grade, and the solvents were high-performance liquid chromatography (HPLC) grade.

Animals. Sixteen male Sprague-Dawley rats from Janvier Laboratories (Le Genest-St-Isle, France) weighing 294 ± 20 g (mean ± standard deviation [SD]) were used for the pharmacokinetic experiments and were divided into two groups: a hypovolemic group (n = 8) and a control group (n = 8). Three extra rats weighing 309 ± 5 g were used to evaluate the impact of hypovolemia on IPM recovery. All animals were acclimatized in wire cages in a 12-h light and 12-h dark cycle for a minimum of 5 days before the beginning of the experiment to allow them to adjust to the new environment. During this period, they had free access to food (A03; Safe, Villemoisson-sur-Orge, France) and water. This work was done in accordance with the Principles of Laboratory Animals Care (25a).

Catheter and probe insertion. On the day before the experiment, the rats were anesthetized by isoflurane (Forene, Abbot, Rungis, France) inhalation (23, 24). Polyethylene cannulas were inserted into the left femoral vein and artery for drug administration and blood sampling, and two CMA/20 probes (polycarbonate; membrane length, 10 mm; CMA microdialysis; Phymep, Paris, France) were inserted into the right jugular vein and the right hind leg muscle as described previously (24). The rats were allowed to recover to a conscious state. During the entire night, the muscle probe was perfused with blank Ringer solution at a flow rate of 0.5 µl · min–1. Food was withdrawn approximately 12 h before the experiment, but the animals had free access to water until the beginning of the experiment.

Impact of hypovolemia on IPM recovery. The experiment for determination of the impact of hypovolemia on IPM recovery was started with retrodialysis by drug period, during which the probes were perfused (CMA 100 microdialysis pump; Phymep) for 60 min at 2 µl · min–1 with Ringer solution containing IPM (10 µg · ml–1) to equilibrate the system. After this equilibration period, microdialysate samples were collected automatically with a CMA/140 Microfraction collector (CMA microdialysis; Phymep) for 50 min by fractions corresponding to 10-min intervals. This was followed by two periods of 30 min, one for hypovolemia induction and the other for stabilization, during which probe perfusion was maintained. Then, during a second collection period, samples were collected over 110 min. To determine in vivo recoveries by loss, the IPM concentrations in the perfusate (Cin) and dialysates (Cout) were determined by HPLC. The in vivo recovery by loss (RLin vivo) was calculated for each interval of time and is expressed as a percentage (1):

(1)

Pharmacokinetic study. (i) Recovery calculations. On the day of the experiment, the experiment started with retrodialysis by drug treatment period, during which the probes were perfused (CMA 100 microdialysis pump; Phymep) at 2 µl · min–1 with Ringer solution containing IPM (10 µg · ml–1) for 60 min to equilibrate the system. After this equilibration period, microdialysate samples were collected automatically with a CMA/140 microfraction collector (CMA microdialysis; Phymep) for 40 min in fractions corresponding to 10-min intervals. In vivo recovery by loss was calculated for each interval of time as described above (equation 1). The mean value obtained from the four individual determinations was calculated to correct the measured dialysate concentrations. A washout period of 60 min with a blank Ringer solution perfusion was allowed before the start of intravenous IPM administration to remove IPM from the probes. The flow rate was maintained at 2 µl · min–1 for the remainder of the study. Directly after collection, dialysates were diluted 1/3 (vol/vol) with a stabilizer (0.5 M HEPES buffer, pH 6.8; ethylene glycol; HPLC-grade water [1:0.5:0.5; vol/vol/vol]).

(ii) Hypovolemia induction and determination of plasma total protein concentrations. During the washout period, hypovolemia was induced in rats (n = 8) by removing 40% of the initial blood volume (assumed to be 60 ml · kg–1) (5) in six increments (increasing volumes) over 30 min. The first increment was used to measure the total protein concentration before hypovolemia. Two extra arterial blood samples (about 0.5 ml, with compensation) were withdrawn to measure total proteins immediately before IPM infusion and at the end of the experiment. These three blood samples were collected in heparinized tubes and were then centrifuged at 3,000 rpm for 10 min at 4°C. The supernatants were kept frozen at –20°C until protein determinations.

(iii) Imipenem administration. Thirty minutes after removal of the last blood sample, an intravenous infusion of IPM (Tienam) at a dose of 70 mg · kg–1 and an infusion rate of 3 ml · h–1 was performed over a 30-min period, which corresponded to an injection volume of 1.5 ml.

(iv) Microdialysis experiment. In each group, 10 min after the beginning of intravenous IPM administration (which was the time needed to flush the dead volume), the dialysates in muscle tissue and blood were collected over 120 min at 5-min intervals during the first 50 min and at 10-min intervals during the last 70 min. Directly after collection, the microdialysis dialysates were diluted (1:3 [vol/vol] for dialysates collected at 5-min intervals and 1:2 [vol/vol] for the rest of the intervals) with a stabilizer (0.5 M HEPES buffer, pH 6.8; ethylene glycol; HPLC-grade water [1:0.5:0.5; vol/vol/vol]).

IPM analysis. Analysis of IPM in the dialysates was performed by an adaptation of a previously described HPLC assay (11, 12, 24). Standard curves were prepared with IPM in water at concentrations ranging from 0.78 to 50 µg · ml–1. The diluted microdialysates were directly injected onto a Nucleosil C8 column (250 by 0.4 mm [inner diameter]; Interchim, Monluçon, France) in association with a Nucleosil C8 precard (5 µm; Interchim). The chromatographic system consisted of a Shimadzu (Croissy Beaubourg, France) LC-10AT pump and a Waters 717 plus autosampler at 4°C connected to a UV detector (SPD 10A; Shimadzu) at 313 nm. Data were recorded and analyzed on a Kromasystem integrator (Bio-Tek, St. Quentin en Yvelines, France). The mobile phase consisted of 0.2 M aqueous borate buffer, pH 7.2, containing 10% (vol/vol) methanol, and the flow rate was 1 ml · min–1. The retention time of IPM was equal to 5.5 min. The between-day variability of IPM was characterized at 5 µg · ml–1, with a coefficient of variation equal to 7.5% (n = 34) and an accuracy equal to 98.5% (n = 34).

Noncompartmental pharmacokinetic analysis. Pharmacokinetic parameters were determined for each individual rat by a noncompartmental approach, according to standard procedures and with the software WinNonLin 4.0.1 (Pharsight Corporation, Mountain View, Calif.). Total body clearance (CL) was calculated as CL = dose/AUCblood, where AUCblood is the total area under the free blood concentration-versus-time curve calculated by using the trapezoidal rule. The area remaining under the curve after the last measured concentration, C(last)blood, was determined from C(last)blood/kel,blood. The elimination rate constant (kel,blood) and its corresponding half-life (t1/2,blood) were estimated by least-squares fit of the datum points (log concentration-time) in the terminal phase of the decline. The volume of distribution (V) was also estimated from CL/kel,blood. The AUC and t1/2 for muscle tissue were also estimated by the same procedure and are referred as AUCmuscle and t1/2,muscle, respectively. Note that although microdialysis allows determination of the unbound drug concentrations in plasma water or tissue extracellular fluid, for simplicity, the subscripts (blood or muscle) refer to the medium in which the probe was implanted.

Statistical analysis. Concentrations were expressed as means ± SDs. Comparisons of AUC, t1/2, and the maximum concentration (Cmax) obtained in blood and muscle in the same rat were performed by a paired t test, with significance being a P level of <0.05. Comparisons of AUC, t1/2, Cmax, CL, V, and the ratio of AUCmuscle/AUCblood between the two groups were performed by an unpaired t test, with significance being a P level of <0.05. Comparisons of plasma total protein concentrations before and after hypovolemia were performed by a paired t test, with significance being a P level of <0.05.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Impact of hypovolemia on IPM recovery. Hypovolemia had no apparent effect on IPM recovery by loss, which was essentially constant throughout the 220-min study duration, as illustrated in Fig. 1 for a representative rat.



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  		FIG. 1. Relative recovery by loss of IPM (in percent) in blood and muscle tissue estimated before and after hypovolemia after probe perfusion with IPM solution (10 µg · ml–1) at a flow rate of 2 µl · min–1 in a representative rat.

 
Pharmacokinetic study. Plasma total protein concentrations were constant throughout the study duration in control rats (Table 1), and hypovolemia induced a statistically significant reduction in plasma total protein concentrations, which then remained unchanged for the rest of the study (Table 1).


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  		TABLE 1. Total plasma protein concentrations in control rats at the beginning and at the end of the experiment and in hypovolemic rats before the induction of hypovolemia, 30 min after the end of hypovolemia, and at the end of the experiment

 
RLin vivo varied between 16.1% ± 1.7% and 40.8% ± 5.7% in blood and between 15.7% ± 0.8% and 35.2% ± 4.1% in muscle tissue.

Control group. The decay of the free IPM concentrations in blood and muscle tissue with time were monoexponential, and the concentration profiles were almost superimposed (Fig. 2a 1). The concentrations at the end of the infusion were equal to 115 ± 23 and 111 ± 14 µg · ml–1 in blood and muscle tissue, respectively (P > 0.05) (Fig. 2b1 and c1). The values of the pharmacokinetic parameters obtained for the control group are presented in Table 2. Half-lives and AUCs were not statistically different between blood and muscle, and AUC ratios were close to 1 (Table 2).



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  		FIG. 2. Unbound IPM concentrations in control rats (n = 8) (left panels) and hypovolemic rats (n = 8) (right panels) after a 30-min intravenous infusion of 70 mg · kg–1 of IPM: superimposed mean concentrations in blood (full circles) and muscle tissue (open circles) in control rats (a1) and hypovolemic rats (a2), mean ± SD concentrations in blood in control rats (b1) and hypovolemic rats (b2), and mean ± SD concentrations in muscle tissue in control (c1) and hypovolemic rats (c2).

 

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  		TABLE 2. Values of pharmacokinetic parameters obtained in blood and muscle tissue of control rats and hypovolemic rats after a 30-min intravenous infusion of imipenem at a dose of 70 mg · kg–1

 
Hypovolemic group. The decay of free IPM concentrations in blood and muscle tissue with time were monoexponential, and the concentration profiles were also virtually superimposed (Fig. 2a2), with the concentrations at the end of infusion not being statistically different, and were equal to 132 ± 23 and 125 ± 22 µg · ml–1 for blood and muscle tissue, respectively (Fig. 2b2 and c2). The values of the pharmacokinetic parameters obtained for the hypovolemic group are presented in Table 2. Half-lives and AUCs were not statistically different between blood and muscle tissue, with AUC ratios still being close to 1 (Table 2). However, the AUCs and half-lives of IPM in each tissue were significantly higher in the hypovolemic group than in the control group (Table 2). Clearance was significantly decreased by 23% on average in the hypovolemic group compared to that in the control group (11.4 ± 2.1 ml · min–1 kg–1 versus 14.8 ± 2.4 ml · min–1 kg–1). The volume of distribution was not significantly different between groups (318 ± 48 ml · kg–1 in the hypovolemic group and 325 ± 67 ml · kg–1 in the control group).


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In pharmacokinetics, passive bidirectional diffusion is usually considered to govern the drug distribution within most soft tissues, which means that at equilibrium the unbound concentrations in blood and tissue extracellular fluids (ECFs), and therefore, the corresponding AUCs, should be identical, in theory (29). 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. Yet, similar free concentrations in blood and soft tissues have not always been observed experimentally (7, 14, 20, 21). Several phenomena can be proposed to explain these observations. One is the presence of active efflux transport systems, which have been proposed as an explanation for the limited muscle tissue distribution of norfloxacin (14). Such systems are found in specific tissues or organs, such as the brain, and are responsible for tissue AUC-to-blood AUC ratios less than unity (3, 23); they are also equal to the corresponding influx distribution-to-efflux distribution clearance ratios (3, 33). However, there is no evidence to support the presence of such systems in soft tissues, such as muscle tissue. Alteration of local blood flow, capillary density, and capillary permeability were also mentioned as explanations for the cefpodoxime tissue distribution factor, which ranges from 0.5 to 0.7 (20, 21). Finally, drug degradation within tissue was proposed as an explanation for the limited tissue distribution of cefaclor (7). Interestingly, it should be kept in mind that this is not related to distribution. In relation to this explanation is the fact that drug disappearance from a physiological liquid such as cerebrospinal fluid due to turnover could also contribute to AUC ratios less than unity (3, 27). Yet, one should keep in mind that such situations should be the exception, since, according to basic pharmacokinetic concepts, peripheral ECF tissue AUC-to-blood AUC ratios should be equal to unity, as a general rule (29).

In order to address these issues under optimal conditions, we have recently combined microdialysis in both blood and tissues to measure free antibiotic concentrations (24). The advantages of this approach are that it allows direct determination of free blood concentrations but also allows multiple concentration determinations without blood sampling, which is particularly important when blood volume must be controlled, as was the case with this experimental model of hypovolemia. Using this approach, we have recently demonstrated that free IPM concentrations and AUCs in blood and muscle tissue, as well as lung ECFs of rats (24), are virtually similar, which was confirmed during the present study, at least for blood and muscle tissue. Yet, this finding contradicts the results of Tegeder et al. (31), who reported a mean total plasma AUC-to-free tissue AUC ratio of 2 for healthy subjects, which corresponds to a free tissue AUC-to-total plasma AUC ratio of 0.5. When it is considered that all of the imipenem was unbound to protein (30), a virtually similar value would be obtained for the free tissue AUC-to-free blood AUC ratio. Yet, there is no explanation for such a major discrepancy.

The experimental model of hypovolemia used throughout this study with removal of 40% of the blood volume, which corresponded to about 5 ml of blood, was adapted from the model of de Paepe et al. (8, 9, 10). With the initial model, 30% of the blood volume was removed. However, this was considered a model of mild hypovolemia, and based upon our previous experience (19), we decided to remove 40% of the blood volume for the present study. Under these conditions, a statistically significant reduction of IPM clearance was observed, most likely due to renal blood flow impairment. However, hypovolemia had no effect on the IPM volume of distribution (Table 2), which differed from our previous findings (19). Yet, a much higher IPM dose was administered in the previous study, and this led to sustained seizures, which could have had an effect on the total body water content and, therefore, the IPM distribution. Like other amino-ß-lactam antibiotics, IPM distributes within the total extracellular body water, which is estimated to be 297 ml · kg–1 in rats (5). Accordingly, the IPM volume of distribution estimate (either total or unbound, since protein binding is limited) was always consistent with that value and, in particular, was consistent with that value in the present study (Table 2). Because the intravascular water content corresponds to about 10% of the total extracellular body water content, removal of 40% of the blood volume would initially reduce the total extracellular body water content by only 4%, which would hardly be detectable. Accordingly, no alteration in the IPM volume of distribution could be observed in hypovolemic rats.

As another potential effect on drug distribution, blood removal should lead to shifts in volume between the intravascular and the extravascular spaces. These redistribution processes have been proposed as a possible explanation for the altered volume of distribution of piperacillin in critical care patients (2). However, volume shifts alone should have an effect on the relative amounts of IPM present within the intravascular and extravascular spaces but not on the unbound drug concentrations, which at equilibrium should be equal within the intravascular and extravascular spaces, independently of the corresponding volumes (29). It was therefore important to confirm experimentally this theoretical expectation by using microdialysis and by demonstrating that free IPM concentrations in muscle tissue ECFs and blood were always similar, meaning that hypovolemia did not result in lower tissue antibiotic concentrations, as it could have been suggested in a previous study, in which it was inappropriately attributed to altered blood flow (31).

Yet, altered tissue blood flow in nonvital organs, such as muscle tissue, which could typically be reduced by up to 50% during hypovolemia (13), constitutes another factor with a potential effect of drug distribution. The rate of distribution of IPM in muscle tissue ECF is more likely limited by tissue blood flow rather than membrane permeability, just as the converse is probably true in brain tissue (29). 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).

In conclusion, the present study has demonstrated that the distribution of IPM in soft tissues was not noticeably altered by using an experimental model of hypovolemia in rats, whereas its elimination characteristics were modified. More importantly, free IPM AUCs determined in blood and muscle tissue ECF were identical in both control and hypovolemic rats, in agreement with basic pharmacokinetic concepts.


   ACKNOWLEDGMENTS
 
We thank Pharsight Corporation for the free supply of WinNonLin through the PAL program.

We thank Brunet Bertrand (Laboratoire de Biochimie, CHU Poitiers) for his assistance during protein determination.


   FOOTNOTES
 
* Corresponding author. Mailing address: EA 3809, Pôle Biologie Santé (PBS), Médecine-Sud, Niveau 1, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France. Phone: 33-5-49-45-43-79. Fax: 33-5-49- 45-43-78. E-mail: william.couet{at}univ-poitiers.fr. Back


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Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Antimicrobial Agents and Chemotherapy, December 2005, p. 4974-4979, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4974-4979.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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