1 Division of Pharmaceutics and Industrial Pharmacy, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201; 2 Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
Received 16 October 2002; returned 27 March 2003; revised 8 April 2003; accepted 28 May 2003
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Abstract |
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Materials and methods: IPK experiments (34 per treatment group) were conducted using male SpragueDawley rats (250350 g). Dose proportionality studies were carried out over a pentamidine dosing range of 804000 µg, designed to target initial perfusate concentrations from 1 to 50 µg/mL. Separate interaction experiments were conducted between pentamidine (800 µg) and tetraethylammonium (dose 8000 µg) or dideoxyinosine (dose 80 µg). Inulin was used as a glomerular filtration rate (GFR) marker. Control (drug-naive) perfusions were also carried out. Pentamidine was analysed in perfusate, kidney and urine samples by HPLC. Inulin was measured by a colorimetric method.
Results: Pentamidine CLR (1.1 ± 0.6 to 0.05 ± 0.03 mL/min) and excretion ratio (3.6 ± 1.5 to 0.56 ± 0.15) significantly decreased over the range of doses studied. Significant reductions in viability parameters (GFR, Na reabsorption) were noted in kidneys perfused with high dose pentamidine (4000 µg). Tetraethylammonium co-administration reduced pentamidine renal excretion, resulting in significantly greater kidney accumulation of pentamidine and reduced kidney function. Dideoxyinosine administration had minimal effects on pentamidine disposition.
Conclusions: Pentamidine renal transport involves a combination of mechanisms (filtration, secretion and passive reabsorption). Dose proportionality studies demonstrated non-linear excretion of pentamidine. Inhibition of pentamidine renal clearance by tetraethylammonium was consistent with decreased luminal transport. The detrimental effects of pentamidine on kidney function were the result of significant kidney accumulation of drug. The potential exists for drugdrug interactions between pentamidine and organic cations, increasing the risk of drug-induced nephrotoxicity.
Keywords: pentamidine, renal transport, renal excretion, nephrotoxicity, kidney accumulation
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Introduction |
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In vivo, pentamidine has a long elimination half-life (>4 days),11 as the compound accumulates significantly in tissues. Pentamidine undergoes extensive hepatic metabolism, with renal excretion accounting for a small fraction (<10%) of the administered dose.12,13 Despite the fact that pentamidine is nephrotoxic, there is limited information regarding the mechanism(s) contributing to the renal excretion of this medication. There is evidence to suggest that that pentamidine undergoes renal secretion.14 Active secretion represents a potential site for drugdrug interactions in the kidney.15 This raises the potential for altered renal disposition of pentamidine in the presence of other medications, possibly enhancing or reducing the renal toxicity of this compound. Although such interactions are not well documented in the literature, a previous investigation in rats identified several compounds that either enhanced or reduced pentamidine toxicity.16 In another study, the renal clearance of pentamidine in rats was increased in the presence of dideoxyinosine.17
In the present investigation, the renal excretion of pentamidine was studied in the isolated perfused rat kidney (IPK). The IPK is an established model to study the renal disposition of medications.1820 This technique has been utilized over the past two decades and previous investigators have demonstrated a correlation between IPK results and in vivo disposition.21 Overall, the IPK provides an opportunity to conduct studies that are not possible in vivo. This is particularly true for the proposed investigation of pentamidine renal excretion. Because of the compounds extensive extra-renal clearance, whole animal studies would lack the high degree of precision in data analysis that the IPK provides. Moreover, since kidney function is monitored throughout a perfusion experiment, drug-induced kidney toxicity can be identified.
In a previous study, creatinine was shown to alter the excretion of pentamidine in the IPK, resulting in reduced kidney viability.22 The goal of this study was to further elucidate the renal disposition and toxicity of pentamidine excretion through dose-linearity and interaction experiments.
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Materials and methods |
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Pentamidine isethionate, tetraethylammonium, dideoxyinosine, sulfadiazine, BSA, dextran (clinical grade, average molecular weight = 60 00090 000 Da), inulin (from chicory root), glucose, glucose (Trinder) reagent, and L-amino acids were obtained from SigmaAldrich Company (St. Louis, MO, USA). HPLC grade acetonitrile and anthrone were purchased from EM Chemicals (Gibbstown, NJ, USA). Sulphuric acid and monobasic potassium phosphate were purchased from VWR Scientific (West Chester, PA, USA).
Animals
Male SpragueDawley rats (250350 g) were used for perfusion experiments. The rats were purchased from Harlan SpragueDawley (Indianapolis, IN, USA). Rats were housed in stainless steel cages and fed a standard diet including water ad libitum. The Institutional Animal Care Committee of Long Island University approved the protocol for this investigation.
Isolated perfused rat kidney preparation
The surgical technique employed was the Bowman modification23 of the Nishiitsutsuji-Uwo procedure.24 Anaesthesia was induced with an intraperitoneal injection of sodium pentobarbital (40 mg/kg). A midline incision was made and the renal segment of the aorta exposed. A ligature was passed under the right renal artery close to the aorta, and distal and proximal ligatures placed around the superior mesenteric artery. The right ureter was catheterized with polyethylene (PE-10) tubing, in order to facilitate urine collection. A cannula was then threaded through the mesenteric artery, across the aorta, and into the right renal artery in situ. The ligatures were tied, securing the cannula in place. The right kidney was then excised from the animal, trimmed of adhering tissue and transferred to the in vitro recirculating perfusion apparatus.
Perfusion of the kidney proceeded according to the method described by Bowman.25 Perfusate consisted of the following: KrebsHenseleit buffer (pH 7.4), 4.00% BSA, 1.67% clinical grade dextran, 100 mg/dL glucose, 60 mg/dL inulin and a 13 mM amino acid solution. Inclusion of amino acids improves viability of the preparation.26 The volume of recirculating perfusate was 80 mL. Dextran was added to maintain appropriate oncotic pressure of the perfusate.27
Study groups
Dose-linearity studies were carried out using a range of pentamidine doses from 80 µg to 4000 µg (80, 400, 800 and 4000 µg). Drug was added as a bolus dose to reach target initial perfusate concentrations of 1, 5, 10 and 50 µg/mL respectively. Interaction studies were carried out between pentamidine and tetraethylammonium (dose 8000 µg, targeted perfusate concentration 100 µg/mL) or dideoxyinosine (dose 80 µg, targeted perfusate concentration 1 µg/mL).28 The dose of pentamidine used for all interaction studies was 800 µg. Control (drug-naive) perfusions were conducted to identify any drug-induced changes in kidney function. Three or four perfusion experiments were conducted for each study group except the dideoxyinosine interaction experiments (n = 2).
Study design
Following kidney excision and transfer to the recirculating perfusion system, a stabilization period (1020 min) preceded any pharmacokinetic experimentation. Drug was then added, and perfusate (0.8 mL) sampled initially at 5 min and every 10 min thereafter. Urine was collected at 10 min intervals over the entire experiment (120 min). For interaction studies, interactant was added after the stabilization period. After a 10 min distribution period, pentamidine was then added.
Volume lost due to sampling or urine excretion was replaced as needed with a 50:50 mixture of perfusate and deionized water. Upon completion of a perfusion experiment, the kidney accumulation of pentamidine was determined using a previously described method.22 All samples were stored frozen at 20°C before analysis.
Aliquots of both perfusate and urine were analysed for sodium (ion specific electrode), glucose (glucose oxidase reaction, Sigma Diagnostic Test Kit 315, Sigma Chemical Co.) and inulin (anthrone colorimetric assay).22 Parameters monitored to assess kidney function throughout an IPK perfusion included glomerular filtration rate (GFR, estimated as inulin clearance), fractional reabsorption of glucose (FRGLU), fractional reabsorption of sodium (FRNa), urine flow rate, and urine pH. Perfusion pressure was maintained at 100 ± 10 mmHg by adjusting perfusion flow rate as necessary.
Protein binding determination
The perfusate binding of pentamidine was determined by ultrafiltration. Aliquots (1 mL) of perfusate were sampled during each perfusion (at 15 and 85 min post-dose). Samples were added to Amicon Centrifree micropartition systems (Millipore Corporation, Bedford, MA, USA) and centrifuged at 1500g for 15 min. The resultant ultrafiltrates containing free drug were stored at 20°C before analysis.
Analytical method for pentamidine
Pentamidine was measured in all samples using a validated HPLC assay.22 The HPLC system consisted of a system controller (SCL-6B, Shimadzu Scientific Instruments, Columbia, MD, USA), an autoinjector (SIL-6B, Shimadzu Scientific Instruments, Columbia, MD, USA), and a scanning ultraviolet detector (SPD-10AV UVVis, Shimadzu Scientific Instruments, Columbia, MD, USA). Output was processed using a Hewlett-Packard personal computer with Turbochrome integration software (version 4.0, Perkin Elmer Instruments, Norwalk, CT, USA) and a PE Nelson 900 series interface. Sulfadiazine was used as an internal standard. Separation was accomplished with an Altima (2.1 x 250 cm) base deactivated C-18 column (Alltech Associates, Deerfield IL, USA) and a mobile phase consisting of 76% 0.025 M monobasic potassium phosphate solution (pH adjusted to 3.2 with dilute phosphoric acid) and 24% acetonitrile. The mobile phase flow rate was 1 mL/min and the detection wavelength was 270 nm.
The sample preparation procedure was as follows: 25 µL of internal standard solution (25 µg/mL of sulfadiazine stock solution) was added to a 250 µL aliquot of sample (perfusate, urine). Then 250 µL of zinc sulphate (1%) was added, and the mixture was vortexed for 1 min and centrifuged at 8000g for 10 min. A 100 µL aliquot of the resultant supernatant was injected into the HPLC system.
Data analysis
Pentamidine CLR was calculated as the ratio of cumulative drug excretion and AUC (090 min). AUC (090 min), representing AUC over the period of sample collection post-dose, was calculated using the trapezoidal rule. Filtration clearance (CLFILT) was defined as the product of glomerular filtration rate (GFR) and unbound fraction of pentamidine in perfusate (fu). Excretion ratio (XR), an indication of net mechanisms of elimination, was calculated as the ratio of CLR and CLFILT.
Statistical analysis
Mean parameter estimates of IPK viability criteria for control and drug treatment groups were compared using analysis of variance (ANOVA). Dunnetts test was used to identify those study groups that differed from control perfusions in terms of viability criteria. Consequently, alterations in kidney function induced by pentamidine administration were determined. Likewise, mean values for pentamidine renal elimination parameters were compared using ANOVA. Post-hoc analyses were once again used to identify differences among the various treatment groups in terms of pentamidine kidney disposition.
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Results |
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Table 1 provides a comprehensive list of the parameters utilized to assess the viability of the perfused kidney. The data are presented as mean (S.D.) of results obtained from dose-proportionality studies with pentamidine. Collectively, these parameters are indices of renal function in the IPK preparation. Based on the control (drug-naive) study group, good renal function was maintained in this investigation. The values listed in Table 1 compare favourably with those reported previously.2931 However, there was evidence of detrimental effects of pentamidine on kidney function. At the highest dose studied (4000 µg), significant reductions in GFR, glucose reabsorption and sodium reabsorption were observed (P < 0.05).
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Table 4 contains the viability data for the interaction studies. In perfusions with both tetraethylammonium and pentamidine, renal function was significantly impaired (P < 0.05) as reflected in GFR, FRGlu, and FRNa. Since pentamidine-associated nephrotoxicity was observed at high doses (4000 µg, Table 1), these findings are consistent with the detrimental effects of pentamidine as a result of increased kidney accumulation. Whereas this was confirmed by the renal excretion data (described below), one other possibility needed to be ruled out, that is, tetraethylammonium-induced kidney effects. In order to dismiss this factor, an IPK experiment was carried out to study kidney function in the presence of tetraethylammonium alone. As seen in Table 4, tetraethylammonium administration alone had no effect on kidney viability. This suggests, therefore, that the toxic effects of pentamidine were manifested by tetraethylammonium effects on pentamidine transport.
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The renal excretion parameters for pentamidine in the presence and absence of interactant are compared in Table 5. Tetraethylammonium significantly reduced (P < 0.05) CLR and cumulative urinary excretion (% dose) of pentamidine, consistent with inhibition of pentamidine secretion. Surprisingly, AUC was significantly lower in the presence of tetraethylammonium. Pentamidine kidney accumulation was significantly enhanced (P < 0.05) by co-administration of tetraethylammonium.
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Modelling the relationship between kidney accumulation and GFR
In this investigation, GFR was identified as an indicator of pentamidine nephrotoxicity. Moreover, reductions in GFR appeared to correlate with the extent of pentamidine accumulation in the kidney. The IPK technique allowed for estimation of the amount of pentamidine accumulated in the kidney. The renal accumulation of pentamidine was estimated via mass balance analysis using a simple relationship:
Xk = X0 Xp Xu
where Xk and Xp represent the amount of drug in the kidney and perfusate, respectively at the end of each collection period. X0 is the amount present in the reservoir at the beginning of each experiment (i.e. the administered dose) and Xu is the cumulative amount excreted in the urine at the end of each collection period. The validity of the mass balance approach was confirmed by direct measurement of the kidney uptake of pentamidine. Mass balance predictions of pentamidine kidney accumulation correlated closely with the amount of pentamidine recovered from the kidney post-perfusion across all treatment groups (recovery > 92%, unpublished results). Consequently, the relationship between GFR and kidney accumulation (Xk) was analysed using an inhibitory EMAX model,32 described by the following equation:
GFR = Baseline [(EMAX x Xk)/(EX50 + Xk)]
where Baseline represents baseline GFR (in the absence of pentamidine); EMAX is the maximum drug-induced effect on GFR; Xk is the kidney accumulation of pentamidine (µg), and EX50 is the accumulation of pentamidine at 50% of maximal effect.
The model describes the reduction in GFR from baseline as a function of pentamidine accumulation. The equation was fitted to data pooled from all treatment groups using WinNonlin (Pharsight Inc., Mountain View, CA, USA). The results are depicted in Figure 1. A good fit of the model to the data was obtained based upon criteria that included randomness of scatter of residuals and standard error of model parameters. Figure 1 clearly demonstrates an association between pentamidine and reductions in GFR. Estimates of the model parameters were as follows: Baseline = 0.68 ± 0.037 mL/min; EMAX = 0.58 ± 0.034 mL/min, EX50 = 259 ± 57.1 µg.
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Discussion |
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The apparent toxic effects of pentamidine on kidney function demonstrated in this investigation are consistent with observations in rats that tubulotoxicity of pentamidine was dose-related.16 To this end, the present findings demonstrate a correlation between the extent of kidney sequestration of pentamidine and perturbations in kidney function, most notably GFR (Figure 1).
Organic cations are transported by the proximal tubule via a multi-step process.33,34 As depicted in Figure 2, uptake from the plasma into the tubular cell proceeds by facilitated diffusion, the driving force being the electrochemical gradient across the basolateral membrane (inside negative potential difference). At least two distinct organic cation transporters have been identified on the basolateral membrane, OCT1 and OCT2.35,36 Once inside the tubular cell, intracellular sequestration can result in extensive drug accumulation. In addition to binding to cytosolic proteins, organic cations can also accumulate in vesicular compartments (e.g. endosomes and lysosomes). The acidic pH of these organelles can "ion trap" cationic compounds that enter via passive diffusion. Luminal transport of cationic compounds into the urine is active, mediated by two distinct transport mechanisms: an organic cation/proton exchange transporter (OCTN) and the multidrug resistance transporter, P-glycoprotein (Pgp).
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As noted in Table 2, 44% of pentamidine was recovered from the kidney at the highest dose administered. Therefore, detrimental effects of pentamidine on GFR can presumably be attributed to this degree of sequestration. Aminoglycosides (e.g. tobramycin, gentamicin) are nephrotoxic compounds that have been shown to accumulate in kidney lysosomes and inhibit lysosomal enzyme activity.37,38 Although the mechanism of pentamidine-induced toxicity has not been established, lysosomal accumulation may be involved. With regard to effects on sodium transport, pentamidine inhibits reabsorption of sodium ions by blocking the luminal sodium ion channels in a manner similar to potassium-sparing diuretics.39 A significant reduction (P < 0.05) in FRNa was observed with the high-dose treatment groups.
In order to further characterize the tubular transport of pentamidine, interaction studies were carried out. Tetraethylammonium, a quaternary ammonium compound, is a widely used probe compound for studying renal organic cation transport. Previous studies have determined that tetraethylammonium is a substrate for both basolateral and luminal organic cation transporters,40,41 but not P-glycoprotein.42 Therefore, tetraethylammonium was used to investigate the role of cation transporters on pentamidine disposition in the IPK.
When co-perfused with tetraethylammonium, detrimental effects of pentamidine on kidney function were observed (Table 4). In these experiments, toxicity was the likely result of tetraethylammonium inhibition of pentamidine luminal transport. This conclusion is based on the associated changes in pentamidine excretion parameters (cumulative excretion, kidney accumulation, AUC) in the presence of interactant (Table 5). In addition to being dose-dependent, pentamidine toxicity was also manifested by co-administration of tetraethylammonium. Interestingly, AUC was significantly lower in the presence of tetraethylammonium. Both pentamidine and tetraethylammonium have high pKa values, and both compounds exist as positively charged ions at physiological pH (7.4). The increased positive charge may have enhanced the facilitated diffusion of pentamidine across the basolateral membrane into renal tubular cells, a process that is driven by membrane potential. Therefore, whereas pentamidine cumulative renal excretion (% dose) was significantly reduced (P < 0.05) by tetraethylammonium, this was not reflected in the perfusate data. Collectively, these observations suggest that the likely site of interaction is the luminal membrane, specifically the organic cation transport system, OCTN. Further studies are needed to confirm this assumption.
In a previous study, the GFR marker creatinine produced similar (although less pronounced) effects on pentamidine disposition and functionality of the IPK.22 Together with the tetraethylammonium results, these interaction studies are potentially relevant to the clinical setting. Whereas concomitant administration with other organic cations may not result in significant changes in the in vivo pharmacokinetic profile of pentamidine (since renal excretion is a minor clearance pathway), such therapeutic combinations may predispose patients to drug-induced kidney toxicity. The potential for this type of drugdrug interaction is often overlooked. Organic cations are compounds whose primary route of clearance is via biotransformation. Nevertheless, interactions among these compounds at the level of the kidney are to be expected. It is important to recognize that clinically significant drug interactions can arise in the kidney, involving compounds that are not significantly excreted into the urine. In the case of pentamidine, inhibition of luminal transport by other medications may predispose patients to toxicity due to increased drug accumulation in the kidney.
An additional series of interaction studies were carried out between pentamidine and dideoxyinosine (a nucleoside analogue). These compounds are co-administered to patients with AIDS. In a previous study in rats, pentamidine CLR increased five-fold in the presence of dideoxyinosine.17 The authors attributed this unexpected finding to dideoxyinosine-induced inhibition of pentamidine tubular reabsorption. An aim of the present research was to further study this interaction in the IPK.
As seen in Table 5, CLR was not altered in the presence of dideoxyinosine. Likewise, cumulative urinary excretion (% dose) and kidney accumulation (% dose) of pentamidine were unchanged. However, pentamidine excretion ratio was significantly increased (although highly variable) and filtration clearance was significantly reduced by dideoxyinosine. This is not surprising since GFR was reduced in this study group. It is unclear whether pentamidine, dideoxyinosine or both compounds caused the reduced GFR in dideoxyinosine-treated perfusions. IPK viability in the presence of dideoxyinosine alone was not investigated. However, the effect on GFR was not accompanied by changes in sodium reabsorption (as observed in other treatment groups). Based on the limited data generated by this IPK study, the results do not support published findings of increased pentamidine clearance in the presence of dideoxyinosine.
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Conclusion |
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Acknowledgements |
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Footnotes |
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Corresponding author. Tel: +1-718-488-1632; Fax: +1-718-780-4586; E-mail: dtaft{at}liu.edu
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References |
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