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NDT Advance Access originally published online on March 29, 2007
Nephrology Dialysis Transplantation 2007 22(7):1963-1968; doi:10.1093/ndt/gfm133
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cytochrome P450 3A5 expression in the kidneys of patients with calcineurin inhibitor nephrotoxicity

Melanie S. Joy1, Susan L. Hogan1, Bawana D. Thompson2, William F. Finn1 and Volker Nickeleit2

1Division of Nephrology and Hypertension, University of North Carolina School of Medicine, UNC Kidney Center and 2Division of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, USA

Correspondence and offprint requests to: Melanie S. Joy, Division of Nephrology and Hypertension, University of North Carolina School of Medicine, UNC Kidney Center, CB 7155, 7005 Burnett Womack Building, Chapel Hill, NC 27599-7155. Email: melanie_joy{at}med.unc.edu



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Background. Nephrotoxicity secondary to calcineurin inhibitors is common in renal transplant recipients, occurring in 76–94% of patients. The role of drug transporters (P-glycoprotein) and drug metabolizing enzymes (cytochrome P450) as predisposing factors toward nephrotoxicity or its prevention has not been thoroughly examined.

Methods. The objective of this study was to analyse cytochrome P450 3A5 (CYP3A5) expression in kidneys of solid organ recipients by immunohistochemistry to determine if there is an association between expression of this enzyme and calcineurin inhibitor toxicity. Transplant recipients were compared with a control group.

Results. Apical tubular plasma membrane staining for CYP3A5 was present in 62% of study and 100% of control biopsies (P = 0.0012). Proximal and distal tubular nuclear staining intensity was similar between groups. Cytoplasmic staining in both the proximal (2.1 ± 0.9 vs 1.4 ± 0.9) and distal (2.8 ± 0.5 vs 1.8 ± 1.1) tubules was greater in the control vs study population specimens, respectively (P = 0.0093 and P = 0.0005, respectively). Regression models that controlled for use of CYP3A inhibiting and inducing medications, age, gender, race and glomerular filtration rate did not predict differences between study groups with regard to staining locations and intensity, except for the cytoplasm of the distal tubule, where intensity of staining was significantly lower in the study group (0.9 ± 0.3; P = 0.002).

Conclusions. This study showed decreased expression of CYP3A5 in nephrotoxic biopsies as compared with a control group. Our data suggest that the relationship between reduced presence of CYP3A5 in the kidney tubules and nephrotoxicity should be further explored to elucidate the role of this enzyme in mediating toxicity.

Keywords: cyclosporine; cytochrome P450; immunohistochemistry; nephrotoxicity; renal transplant recipients; tacrolimus



   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Ciclosporin and tacrolimus are frequently prescribed calcineurin inhibitors to prevent solid organ transplant rejection episodes and are often employed as immunosuppressants for other disorders [1–3]. Nephrotoxicity is the most frequent and severe adverse event that either precludes their use or at least requires close monitoring. Nephrotoxicity secondary to calcineurin inhibitors occurs in liver (52%), heart (20–75%) and kidney (76–94%) transplant recipients [4–7]. This form of nephrotoxicity clinically presents as an elevation in serum creatinine and blood urea nitrogen, as well as disorders of electrolytes, acid-base status, renal endocrine function and urine concentrating ability. Morphologically, structural changes associated with the renal toxicity are found mainly in the tubules, afferent arterioles and glomeruli [8].

Investigators continue to explore the aetiologies for calcineurin inhibitor-related nephrotoxicity [9–11]. The examination of the role of intracellular transport proteins (drug efflux proteins) in modulating calcineurin inhibitor toxicities is appealing given that P-glycoprotein (P-gp) is known to transport both ciclosporin and tacrolimus [12]. We and others [13–15] have reported the presence of P-gp predominantly on the apical membrane of renal tubules. The role of P-gp in regulating the nephrotoxicity of calcineurin inhibitors has also been proposed, given its activity as an export pump on the apical membranes of various tissues [14,16]. It is intriguing to consider the supportive role of the cytochrome P450 drug metabolizing enzyme CYP 3A5 in ameliorating this form of drug-induced nephrotoxicity since this enzyme can metabolize pharmacologically active agents to less active/toxic substances and also co-localizes in the genome and at anatomical locations with P-gp [17]. Additionally, some substrates (including ciclosporin and tacrolimus) are metabolized and transported by CYP3A5 and P-gp, respectively [18]. Lastly, CYP3A5 is primarily found in the anatomical location of the kidneys, where local calcineurin inhibitor metabolism may occur, whereas CYP3A4 and other CYPs are predominantly localized to the liver [19–21].

In our previous study, we showed that P-gp expression was reduced in transplant patients who exhibited structural signs of calcineurin inhibitor nephrotoxicity in comparison with controls, suggesting an association between P-gp and nephrotoxicity associated with these agents [14]. Since the calcineurin inhibitors are substrates for CYP3A5 metabolism in addition to being substrates for P-gp transport, we decided to analyse renal CYP3A5 expression by immunohistochemistry to further elucidate the association between nephrotoxicity secondary to calcineurin inhibitors and the drug disposition-association factor of metabolism. We hypothesized that transplant patients with structural nephrotoxicity would exhibit reduced expression of CYP3A5 in the kidney—suggesting an association between local (renal) metabolism and nephrotoxicity.



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
A HIPPA (Health Insurance Portabilty and Accountability Act) waiver to study existing pathology specimens and medical records was approved by the University Investigational Review Board (IRB). The nephropathology database was reviewed for renal biopsy specimens from solid organ transplant recipients that were coded for calcineurin inhibitor-induced toxicity (i.e. study group). Structural calcineurin inhibitor-induced nephrotoxicity was defined according to the criteria by Mihatsch et al. [8,22,23]. The nephropathological structural criteria used were previously described [14]. A control group of renal biopsy specimens from age-matched patients who lacked any morphological evidence of calcineurin inhibitor-induced toxicity was selected from the nephropathology database. This control group included biopsy specimens from patients with various renal diagnoses including acute interstitial nephritis (3), thrombotic microangiopathy (4), amyloid (1), diabetes mellitus (6), acute cellular rejection (w/o nephrotoxicity) (4), minimal change disease (5) and arterionephrosclerosis (7). All biopsies in the study and control groups showed only minor degrees of tubular damage not >20% of the biopsy cores. Charts of control and nephrotoxic patients were evaluated for demographics, clinical and laboratory data and prescribed medications that are known to induce or inhibit CYP3A. Renal laboratory data of interest including serum creatinine, estimated glomerular filtration rate from the Cockroft–Gault formula [24], and levels of proteinuria were collected at the time of biopsy.

Immunohistochemistry
The immunohistochemistry assay was previously described [14]. Incubations were performed on 5 µ thick sections cut from formalin-fixed and paraffin-embedded tissue cores. Specific to this study, slides were incubated with the primary antibody, rabbit anti-human CYP3A5 polyclonal antibody (Chemicon International, Inc.) 1/5000 in Ventanna solution overnight at 4°C in a humidity chamber. Negative controls were incubated overnight in rabbit Envision + Universal Negative Control (DAKOCytomation). After rinsing with Automation buffer, the slides were incubated in secondary antibody (Envision + HRP Rabbit, DAKOCytomation, Carpinteria, CA) for 30 min at room temperature.

Evaluation of staining
The study and control biopsy specimens were reviewed in a blinded approach by the same nephropathologist (V.N.) in order to limit inter-observer variations. All biopsies showed at least five glomeruli and surrounding cortical parenchyma, insuring adequate insight into tubules. The scoring methods for assessment of CYP3A5 staining were modified from that previously reported for P-gp [16].

Proximal and distal tubular CYP3A5 expression was evaluated and scoring was then differentiated by apical membrane, cytoplasm and/or nuclei. Nuclear and apical staining was denoted as either positive or negative. Cytoplasmic staining was defined by intensity according to 0 (no staining) to 4 (maximum staining). The total percentage of tubular cells in the cortex that stained positive were classified as 1 (≤25%), 2 (>25–50%), 3 (51–75%) and 4 (>76%).

Statistical analysis
Descriptive statistics were defined by means ± SDs, medians and ranges and percentages. Differences in demographics, clinical parameters and immunohistochemistry measures between the study and control groups (including gender, race, diagnosis of diabetes mellitus, presence of CYP3A inhibitors or inducers, CYP3A5 presence in proximal and distal tubules and nuclear and apical staining presence) were compared using Fisher's Exact test for categorical measures. Wilcoxon rank sum tests were used for evaluation of differences in continuous measures between the groups including age, weight, serum creatinine, glomerular filtration rate, proteinuria at biopsy, cytoplasmic staining intensity and total percentage of the renal cortical cells with positive CYP3A5 staining.

Logistic regression modelling for two-level variables and linear regression modelling for continuous measures were used to evaluate differences in measures between groups while controlling for the confounders—gender, race, age, glomerular filtration rate and presence of prescribed CYP3A inducing and inhibiting drugs. Results from univariate statistical tests were used as a guide in selecting variables for multivariable statistical modelling. Variables that had either a statistically significant impact on the measure of interest or a confounding influence on the association of the group (study/control) vs outcome were retained in multivariable models. Since there is no statistical test for confounding, measures that altered the primary univariate association by ≥20% was used as a guideline for keeping variables in the models.

The sample size for this study was determined a priori and was based on the ability to detect statistical differences in the only previous evaluation of similar measures of interest between groups of similar size [16]. Since statistically significant differences were observed between groups with respect to many of the ordinal and continuous primary measures of interest, post hoc evaluation of statistical power and minimum detectable differences were not evaluated. Results with two-sided {alpha} values of ≤0.05 were considered statistically significant. Analysis was performed using SAS version 8 (Cary, NC).



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Acknowledgements
 References
 
Twenty-nine nephrotoxic and 30 control biopsy specimens were analysed (Table 1) [14]. The percentage of patients who were prescribed potential CYP3A inducers was higher in the study (79%) vs control (24%) renal biopsy groups (P < 0.0001). These drugs included hydrocortisone, prednisone, carbamazepine and vitamin D. There were no significant differences between the transplant (21%) and control (17%) groups in the percentage of patients who were prescribed CYP3A inhibitors (P = 0.99). The prescribed drugs listed in the potential inhibitor grouping included diltiazem, fluconazole, trazodone, sertraline, fluoxetine and paroxetine.


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  		Table 1. Patient demographics and clinical laboratory results

 
Figure 1 shows the location and percentage of biopsies with positive CYP3A5 staining for the study and control subjects. Proximal tubular nuclear staining was not statistically different between groups; present in 62% of study vs 77% of control biopsies (P = 0.35). The apical membrane of the proximal tubules stained positive for CYP3A5 in only 62% of study biopsies as compared with 100% of controls (P = 0.0012). Distal tubular nuclear staining was present in 97% of study and control biopsies (P = 0.99). The apical membrane of distal tubules stained positive for CYP3A5 in only 58% of study vs 83% of control subjects (P = 0.0470). Cytoplasmic staining for CYP3A5 occurred in both the proximal (mean score: 2.1 ± 0.9 vs 1.4 ± 0.9) and distal (mean score: 2.8 ± 0.5 vs 1.8 ± 1.1) tubules significantly more frequently in the control specimens vs study biopsies (P = 0.0093 and P = 0.0005, respectively) (Figure 2). The percentage of renal cortical cells that stained positive for CYP3A5 was 98% in the control vs 82% in the study group (P = 0.0581) (Figure 3). Photomicrographs showing representative CYP3A5 staining in the kidney biopsies of study and control subjects is provided in Figure 4.


Figure 1
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  		Fig. 1. Distribution of cytochrome P450 3A5 staining locations. Frequency (%) distribution of positive cytochrome P450 3A5 staining at each documented location in the kidney biopsy specimens of control and nephrotoxic transplant groups. PT: proximal tubule; DT: distal tubule. *Statistically significant difference between nephrotoxic and control biopsies at {alpha} < 0.05.

 

Figure 2
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  		Fig. 2. Tubular cytoplasmic staining. Cytoplasmic staining was defined by intensity according to 0 (no staining) to 4 (maximum staining). (A) Represents cytoplasmic staining in the proximal tubule in the control and nephrotoxic transplant biopsies. (P = 0.0093). Error bars represent the minimum and/or maximum values. Control group: minimum = 0, 25th percentile = 1.0, median = 2.2, 75th percentile = 3.0, maximum = 3.0. Nephrotoxicity group: minimum = 0, 25th percentile = 1.0, median = 1.0, 75th percentile = 2.0, maximum = 3.0. (B) Represents cytoplasmic staining in the distal tubule in the control and nephrotoxic transplant biopsies. (P = 0.0005). Error bars represent the minimum and/or maximum values. Control group: minimum = 2.0, 25th percentile = 2.5, median = 3.0, 75th percentile = 3.0, maximum = 4.0. Nephrotoxicity group: minimum = 0, 25th percentile = 1.0, median = 2.0, 75th percentile = 3.0, maximum = 4.0. *Denotes the median values on the graph.

 

Figure 3
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  		Fig. 3. Percentage of Cortical Cells Staining Positive for CYP3A5. The cortical cells staining positive for CYP3A5 was greater in control (98%) vs nephrotoxic transplant biopsies (82%). (P = 0.0581). The total percentage of renal cortical cells that stained positive were classified on a scale of 1 to 4: 1 (≤25% of cells stained), 2 (>25–50% cells stained), 3 (51–75% of cells stained) and 4 (>76% cells stained). Error bars represent the minimum and/or maximum values. Control group: minimum = 3.0, 25th percentile = 4.0, median = 4.0, 75th percentile = 4.0, maximum = 4.0. Nephrotoxicity group: minimum = 1.0, 25th percentile = 2.5, median = 4.0, 75th percentile = 4.0, maximum = 4.0.

 

Figure 4
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  		Fig. 4. Immunohistochemical incubations to detect P450 3A5. (A) Control group: Strong staining (brown) is found in tubules (apical epithelial surfaces, nuclei and cytoplasm). (B) Study group with structural calcineurin inhibitor toxicity: Only minimal staining is noted in rare tubular epithelial cell nuclei. (20x magnification).

 
Regression models that controlled for concomitantly prescribed CYP3A inhibitors and inducers as well as age, gender, race and glomerular filtration rate did not predict statistically significant differences between the patient groups with regard to staining patterns. Multivariable modelling was not possible in assessment of staining differences at the level of the apical membrane of the proximal tubule (100% of the controls had this staining). The difference in the distal tubule apical membrane staining, however, was not found to be different with multivariable modelling: The difference in intensity of staining in the cytoplasm of the distal tubules between groups remained statistically significantly lower (0.9 ± 0.3; P = 0.002, mean difference between the groups) in the nephrotoxic group even when controlling for other factors, while a non-significant difference in intensity of staining in the cytoplasm of proximal tubules was found with the multivariable modelling approach.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Acknowledgements
 References
 
Both ciclosporin and tacrolimus are substrates for the CYP3A subfamily of drug metabolizing enzymes. Ciclosporin is known to be metabolized by CYP3A to at least 25 metabolites. Of these, one of the nine readily identified metabolites also has some activity, but the nephrotoxicity potential has not been reported [25–27]. Ten metabolites of tacrolimus have been identified, with two of these exhibiting some activity [28]. It was thus feasible to explore the association of reduced CYP3A5 and nephrotoxicity in this pilot study since lower expression of CYP3A5 could contribute to more active/toxic levels of pharmacological agents in the kidney tissues.

While it is known that CYP3A4 is predominantly localized to the liver and intestines [29], immunohistochemistry analyses have shown little to no staining for this enzyme in the kidneys [20]. CYP3A5, on the contrary, is predominantly localized to the kidney [20]. Studies evaluating the presence of CYP3A5 in normal kidneys and human renal cell cancer immunohistochemically suggest a predominant intracytoplasmic tubular localization of the enzyme [30]. We extend previous observations by carefully correlating morphological signs of calcineurin inhibitor toxicity with immunohistochemical staining patterns for CYP3A5.

In agreement with previous reports, our results showed that both the proximal and distal tubules stained for CYP3A5 [30]. We found staining signals in the nuclei, apical tubular plasma membranes and the tubular epithelial cytoplasm. Nuclear CYP3A5 expression was similar between study and control biopsy specimens. On the contrary, nephrotoxic specimens showed significantly less CYP3A5 expression in the apical membrane of both the proximal and distal tubules than the controls, underscoring the potential role of CYP3A5 in the development of calcineurin inhibitor nephrotoxicity. This observation is further consolidated by clinical data since nephrotoxic patients (vs controls) more frequently consumed CYP3A-inducing medications, which should have theoretically resulted in over-expression than reduction of CYP3A5.

Our finding regarding the presence of reduced CYP3A5 in the study population requires inquiry regarding the potential role of disease or demography in local tissue enzyme expression patterns. Although our control population represented a diversity of kidney diseases, it is adequately chosen given the retrospective nature of our study. Cases of glomerulonephritis are often accompanied by ‘secondary’ tubulo-interstitial injury and inflammation. Thus, the differences reported in our study cannot simply be explained by significant differences in the degree of tubulo-interstitial injury found in the study groups.

The variables of age, race and CYP3A5 genotype can also be hypothesized to be associated with CYP3A5 expression. Hepatic CYP450 enzyme expression and activity has been reported to decline with age and renal function, and our nephrotoxic patients had lower levels of kidney functions [31–35]. To further investigate the effects of demographic factors and measured level of renal function, we employed multivariable regression models in our study to evaluate the effects of age, race, gender and glomerular filtration rate on biopsy staining locations and intensities. Although controlling for these factors influenced the association between staining patterns and patient group, none was an independent predictor of differences in staining intensities or locations. We did not include genotyping for wild-type and variants of CYP3A5 in our study and hence are unable to associate genotype with nephrotoxicity risks.



   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Acknowledgements
 References
 
Our study is the first to report an association between reductions in tubular CYP3A5 expression in a nephrotoxic calcineurin inhibitor-treated transplant patient population as compared with a control population. This reduction was notably observed in patients treated with a significantly greater number of medications known to induce CYP3A expression. Our preliminary data suggest that further studies should be conducted to determine whether reduced CYP3A5 expression in the kidney might be one factor promoting the development of structural nephrotoxicity secondary to calcineurin inhibitor therapy. Additional study is required to analyse the effects of renal diagnoses, glomerular filtration rate and pharmacogenetics on CYP3A5 expression and/or function in the kidney and other metabolizing organs.



   Acknowledgements
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
References
 
This study was supported by a research grant from the American College of Clinical Pharmacy (ACCP) Research Institute. In addition, this study was presented in part at the 2003 Annual Meeting of the American College of Clinical Pharmacy, Atlanta, GA and at the 37th Annual Meeting of the American Society of Nephrology, St Louis, MO.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

  1. Cattran DC, Appel GB, Hebert LA, et al. Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial. Kidney Int (2001) 59:1484–1490.[CrossRef][ISI][Medline]
  2. Hu W, Liu Z, Shen S, et al. Cyclosporine A in treatment of membranous lupus nephropathy. Chin Med J (Engl) (2003) 116:1827–1830.[Medline]
  3. Cattran DC, Appel GB, Hebert LA, et al. A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int (1999) 56:2220–2226.[CrossRef][ISI][Medline]
  4. Gonwa TA, Morris CA, Goldstein RM, Husberg BS, Klintmalm GB. Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome—experience in 300 patients. Transplantation (1991) 51:428–430.[ISI][Medline]
  5. Nizze H, Mihatsch MJ, Zollinger HU, et al. Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants. Clin Nephrol (1988) 30:248–260.[ISI][Medline]
  6. Zietse R, Balk AH, vd Dorpel MA, Meeter K, Bos E, Weimar W. Time course of the decline in renal function in cyclosporine-treated heart transplant recipients. Am J Nephrol (1994) 14:1–5.[ISI][Medline]
  7. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med (2003) 349:2326–2333.[Abstract/Free Full Text]
  8. Colvin RB, Nickeleit V. Renal Transplant Pathology. In: Heptinstall's Pathology of the Kidney—Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. (2006) Philadelphia: Lippincott Williams & Wilkins. 1349–1490.
  9. Goldfarb DA. Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity. J Urol (2003) 169:2436–2437.[Medline]
  10. Anjaneyulu M, Tirkey N, Chopra K. Attenuation of cyclosporine-induced renal dysfunction by catechin: possible antioxidant mechanism. Ren Fail (2003) 25:691–707.[CrossRef][ISI][Medline]
  11. Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol (2003) 23:465–476.[CrossRef][ISI][Medline]
  12. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem (1993) 268:6077–6080.[Abstract/Free Full Text]
  13. Ernest S, Bello-Reuss E. P-glycoprotein functions and substrates: possible roles of MDR1 gene in the kidney. Kidney Int Suppl (1998) 65:S11–S17.[Medline]
  14. Joy MS, Nickeleit V, Hogan SL, Thompson BD, Finn WF. Calcineurin Inhibitor-Induced Nephrotoxicity and Renal Expression of P-glycoprotein. Pharmacotherapy (2005) 25:779–789.[CrossRef][ISI][Medline]
  15. Tsuruoka S, Sugimoto KI, Fujimura A, Imai M, Asano Y, Muto S. P-glycoprotein-mediated drug secretion in mouse proximal tubule perfused in vitro. J Am Soc Nephrol (2001) 12:177–181.[Abstract/Free Full Text]
  16. Koziolek MJ, Riess R, Geiger H, Thevenod F, Hauser IA. Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients. Kidney Int (2001) 60:156–166.[CrossRef][ISI][Medline]
  17. Inoue K, Inazawa J, Nakagawa H, et al. Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization. Jpn J Hum Genet (1992) 37:133–138.[CrossRef][Medline]
  18. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog (1995) 13:129–134.[ISI][Medline]
  19. Schuetz EG, Schuetz JD, Grogan WM, et al. Expression of cytochrome P450 3A in amphibian, rat, and human kidney. Arch Biochem Biophys (1992) 294:206–214.[CrossRef][ISI][Medline]
  20. Haehner BD, Gorski JC, Vandenbranden M, et al. Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol (1996) 50:52–59.[Abstract]
  21. Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol (1990) 38:207–213.[Abstract]
  22. Mihatsch MJ, Thiel G, Ryffel B. Histopathology of cyclosporine nephrotoxicity. Transplant Proc (1988) 20:759–771.[ISI][Medline]
  23. Mihatsch MJ, Helmchen U, Casanova P, et al. Kidney biopsy findings in cyclosporine-treated patients with insulin-dependent diabetes mellitus. Klin Wochenschr (1991) 69:354–359.[CrossRef][ISI][Medline]
  24. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[ISI][Medline]
  25. Product Information. Neoral (R), cyclosporine. (2001) East Hanover, NJ. In: Pharmaceuticals N, ed.
  26. Product Information. SangCya (TM), cyclosporine. (1998) Menlo Park, CA. In: Corporation SM, ed.
  27. Yee GC. Recent advances in cyclosporine pharmacokinetics. Pharmacotherapy (1991) 11:130S–134S.[Medline]
  28. Product Information. Prograf (R), tacrolimus. (2001) Deerfield, IL. In: Fugisawa USA I, ed.
  29. von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivisto KT. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther (2004) 75:172–183.[CrossRef][ISI][Medline]
  30. Murray GI, McFadyen MC, Mitchell RT, Cheung YL, Kerr AC, Melvin WT. Cytochrome P450 CYP3A in human renal cell cancer. Br J Cancer (1999) 79:1836–1842.[CrossRef][ISI][Medline]
  31. Warrington JS, Greenblatt DJ, von Moltke LL. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther (2004) 309:720–729.[Abstract/Free Full Text]
  32. Guevin C, Michaud J, Naud J, Leblond FA, Pichette V. Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of uremic mediators. Br J Pharmacol (2002) 137:1039–1046.[CrossRef][ISI][Medline]
  33. Leblond FA, Giroux L, Villeneuve JP, Pichette V. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos (2000) 28:1317–1320.[Abstract/Free Full Text]
  34. Dreisbach AW, Japa S, Gebrekal AB, et al. Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther (2003) 73:475–477.[ISI][Medline]
  35. Dowling TC, Briglia AE, Fink JC, et al. Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther (2003) 73:427–434.[CrossRef][ISI][Medline]
Received for publication: 14. 7.06
Accepted in revised form: 16. 2.07


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