HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Liu, S. Articles by Burckart, G. J. Search for Related Content PubMed PubMed Citation Articles by Liu, S. Articles by Burckart, G. J. Social Bookmarking                   What's this?

Effect of Age and Postoperative Time on Cytochrome P450 Enzyme Activity Following Liver Transplantation

From the School of Pharmacy, University of Southern California, Los Angele (Dr Liu, Dr Burckart); the Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville (Dr Frye); and the Center for Clinical Pharmacology (Dr Branch), Department of Pharmaceutical Science (Dr Venkataramanan), and the Thomas E. Starzl Transplantation Institute (Dr Fung), University of Pittsburgh, Pennsylvania. Supported by grant DK34475 from the National Institutes of Health (NIH) and grant 5M01 RR00056 from the National Center for Research Resources/General Clinical Research Centers, NIH.

Address for reprints: Gilbert J. Burckart, University of Southern California, School of Pharmacy, 1985 Zonal Ave, PSC 100, Los Angeles, CA 90033.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
This study evaluates the changes in cytochrome P450 (CYP) enzyme activity in orthotopic liver transplant (OLTx) patients in relation to recipient age and postoperative time. Thirty-eight stable OLTx patients, separated into younger and older age groups, and 21 healthy subjects were given a 5-drug cocktail including chlorzoxazone (CYP2E1), caffeine (CYP1A2), dapsone (CYP3A4), mephenytoin (CYP2C19), and debrisoquin (CYP2D6). The phenotypic indexes were determined for each associated enzyme. Compared to young healthy subjects, the CYP2E1 capacity was significantly increased in younger and older OLTx patients (P < .001), while the CYP2C19 capacity was decreased significantly in younger and older OLTx patients within 30 days postoperatively (P < .01). The CYP2D6 capacity was significantly lower after 30 days postoperatively in older OLTx patients (P < .05). The authors conclude that within 30 days postoperatively, CYP2E1 capacity was markedly elevated in OLTx patients, while 2C19 function was significantly reduced. CYP2D6 capacity was impaired after 30 days postoperatively. Younger and older OLTx patients experienced similar changes in major CYP450 enzyme capacity following liver transplantation.

Key Words: Cytochrome P450 • liver transplantation • phenotype • age

The cytochrome P450 enzymes (CYP) are a superfamily of more than 50 isoforms. The major function of these enzymes is to catalyze phase I biotransformation reactions for xenobiotics. The major human drug-metabolizing CYPs belong to families 1, 2, and 3, among which CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A account for about 65% of the total activity.^1-3 Little information concerning the changes in CYP enzymes after OLTx is available. Thorn et al reported that the mRNA expression from liver biopsies of CYP3A4, 3A5, 2E1, and 1A2 increased during the first year after OLTx.⁴ However, the baseline mRNA expression was taken from the reperfusion period immediately after transplantation and the follow-up study was at 1 year, which makes the change difficult to interpret. In addition, the relationship between hepatic mRNA expression and phenotypic expression of CYP activity is not clear.

The use of metabolic probes to quantitate the phenotypic expression of CYPs is a widely used approach to study changes in drug metabolism. An early study by our group demonstrated that antipyrine clearance normalized rapidly after OLTx.⁵ An extension of these studies included multiple probes for CYP activity. The "Pittsburgh cocktail" contains 5 probe drugs for the above CYP enzymes including 100 mg caffeine, 250 mg chlorzoxazone, 100 mg dapsone, 10 mg debrisoquine, and 100 mg mephenytoin, and it is a noninvasive method to evaluate the in vivo phenotype of these enzymes independently and simultaneously.⁶ Using this approach, we have previously reported the induction of CYP2E1 in the first postoperative month in OLTx patients.⁷ The objective of this study was to examine the changes in the 5 CYP enzyme phenotypes in OLTx patients in relation to recipient age and time after transplantation.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Liver Transplant Patients
This study was approved by the Biomedical Institutional Review Board of the University of Pittsburgh, and all patients undergoing OLTx at the University of Pittsburgh Medical Center were considered to be eligible for study participation. The transplant procedure has been described in detail previously, and the anesthetic used in these patients was primarily isoflurane. All patients were treated with an immunosuppressive regimen of tacrolimus and prednisone, with mycophenolic acid added when necessary. Patients were studied only during periods in which they were considered to be clinically stable. Patients were excluded from the study if they were receiving agents known to produce significant induction (anticonvulsants or rifampin) or inhibition (ketoconazole, fluconazole, cimetidine, or erythromycin) of CYP enzymes or if they had an estimated creatinine clearance of less than 50 mL/min.⁸ Although multiple studies were not possible in all patients, attempts were made to study the subjects in the early posttransplant period (1 to 2 weeks), 1 to 4 months after transplant, and during long-term follow-up (6 to 12 months).

Healthy Subjects
Fourteen young healthy subjects and 7 elderly healthy subjects participated after giving written informed consent. Subjects were instructed to abstain from caffeine or alcohol-containing products for at least 3 days before each study visit.

Study Protocol
After an overnight fast, subjects received the oral 5-drug Pittsburgh cocktail in the General Clinical Research Center. The cocktail included 250 mg chlorzoxazone, 100 mg caffeine, 100 mg dapsone, 100 mg mephenytoin, and 10 mg debrisoquine. None of the 5 agents given in this cocktail influence the metabolism of the other agents given concurrently.⁶ The 5 drugs were taken simultaneously with approximately 240 mL of water. Venous blood was collected through an indwelling catheter before and at 4 and 8 hours after drug administration. Plasma was harvested and stored at –20°C until analyzed. Urine samples were collected before drug administration and for 8 hours after. The total volume was recorded, and an aliquot was stored at –20°C until analyzed.

The following drugs and metabolites were measured by high-performance liquid chromatography techniques: caffeine and paraxanthine in plasma,⁹ chlorzoxazone and 6-hydroxychlorzoxazone in plasma,¹⁰ dapsone and dapsone hydroxylamine in urine,¹¹ debrisoquin and 4-hydroxydebrisoquin in urine,¹² and 4-hydroxymephenytoin in urine.⁶ The within- and between-day coefficients of variation of these assays are less that 10%. Serum and 8-hour urine creatinine determinations provided the basis for the calculation of measured creatinine clearance in each subject.

Data Analysis
Patients were separated into the young OLTx patients group, with age equal to or less than 50 years, and the older OLTx patients group, with age greater than 50 years. Fifty years of age was chosen because of the previously published association of poor outcomes in liver transplant patients older than 50.^13,14 Subjects were excluded from analysis if they had a measured creatinine clearance of less than 40 mL/min. The concentration of paraxanthine (1,7 dimethylxanthine) divided by the concentration of caffeine in the 8-hour plasma sample was used to assess CYP1A2 activity. The ability to hydroxylate chlorzoxazone (CYP2E1) was estimated by the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio at 4 hours. The ability to N-hydroxylate dapsone (CYP3A) was estimated by the urinary recovery ratio HAD/(HAD + DDS), in which HAD is the urinary recovery of dapsone hydroxylamine in an 8-hour urine sample and DDS is the 8-hour urinary recovery of dapsone. The activity of CYP2D6 was estimated by use of the debrisoquin recovery ratio: HDB/(HDB + DB), where HDB and DB are the urinary recoveries of 4-hydroxydebrisoquin and debrisoquin in 8 hours, respectively. The total urinary recovery of 4-hydroxymephenytoin was used as the phenotypic measure of CYP2C19 activity.⁶

Statistical Analysis
All phenotypic trait measure estimates in OLTx patients and healthy control subjects were compared by nonparametric 1-way ANOVA (Kruskal-Wallis test) and Dunns posttest. The differences were considered statistically significant when P .05. All calculations were performed using PRISM software, version 4.00 (Graphpad Software Inc, San Diego, Calif).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Thirty-eight liver transplant patients were recruited into this study. The reasons for OLTx included hepatitis B and C (10 young OLTx patients and 5 older patients), autoimmune diseases (3 young OLTx patients and 8 older patients), and other diseases affecting the liver (5 young OLTx patients and 7 older patients). Two patients were studied on 5 separate occasions, 2 patients were studied 4 times, 4 patients were studied 3 times, 9 patients were studied twice, and 21 patients were studied 1 time. There was a total of 69 patient studies, among which 12 patient studies had to be excluded from analysis because the measured creatinine clearance was less than 50 mL/min. The demographics of the subjects who were included in the analysis are presented in Table I. The groups were analyzed as independent from one another since the statistical analysis after we deleted repeat studies demonstrated that the observations were unchanged.

CYP2E1 enzyme activity as measured by the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio at 4 hours was significantly higher in the young OLTx patients within 30 days after transplantation (mean ± SD, 6.4 ± 5.2), compared to either young healthy controls (0.8 ± 0.3, P < .001) or elderly healthy subjects (0.9 ±0.2, P < .05; Figure 1). Older OLTx patients also had a markedly elevated ratio within the first 30 days postoperatively (5.2 ± 3.7, P < .001) compared to young healthy controls, although this difference was not significant when compared to the elderly controls. After the first month postoperatively, the chlorzoxazone metabolic ratio in young OLTx patients remained high (4.5 ± 5.2), and the difference was significant compared to young healthy subjects (P < .01). However, for older OLTx patients after 30 days postoperatively, the ratio decreased (1.0 ± 0.7) to approximately that of the control subjects. There were no significant differences in CYP2E1 activity between young and older OLTx patients both within and after 30 days postoperatively.

View larger version (22K): [in this window] [in a new window]   Figure 1. The chlorzoxazone metabolic ratio in young and older orthotopic liver transplant patients, within and after 30 days postoperatively and the young and elderly healthy control subjects. Differences between groups are designated as #P < .001, $P < .01, *P < .05.

View larger version (24K): [in this window] [in a new window]   Figure 2. The urinary recovery of 4-hydroxymephenytoin in young and older orthotopic liver transplant patients, within and after 30 days postoperatively, and the young and elderly healthy control subjects. Differences between groups are designated as #P < .001, $P < .01.

CYP1A2 enzyme activity as measured by the caffeine metabolic ratio was not significantly different between the OLTx patients and healthy control groups (Figure 3). No difference was observed when comparing young and older OLTx patients for CYP1A2 activity.

View larger version (25K): [in this window] [in a new window]   Figure 3. The caffeine metabolic ratio in young and older orthotopic liver transplant patients, within and after 30 days postoperatively, and the young and elderly healthy control subjects.

View larger version (28K): [in this window] [in a new window]   Figure 4. The debrisoquin recovery ratio in young and older orthotopic liver transplant patients, within and after 30 days postoperatively, and the young and elderly healthy control subjects. Differences between groups are designated as *P < .05.

View larger version (28K): [in this window] [in a new window]   Figure 5. The dapsone recovery ratio in young and older orthotopic liver transplant patients, within and after 30 days postoperatively, and the young and elderly healthy control subjects. Differences between groups are designated as *P < .05.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
In the early years of liver transplantation, the upper age limit for patients receiving OLTx was 45 to 55 years old. However, the age limitation has been expanded given recent results demonstrating that OLTx in patients older than 60 years can be accomplished safely.¹⁶ In 2003, there were a total of 5671 liver transplant patients, among whom 2738 (48%) were 50 to 64 years old and 473 (8%) were older than 65 years. The putative aging-related physiological changes that may affect drug clearance include a decrease in renal blood flow and glomerular filtration rate, a decrease in hepatic mass/blood flow,¹⁷ andanincrease inadipose tissue and an increase in lean body mass relative to total body mass, which may alter the distribution volume of lipophilic drugs.¹⁸ The clearance of many commonly used drugs metabolized by CYP enzymes decreases with aging, but many studies have suggested that the biotransformation capacity of these CYP enzymes is maintained in the healthy elderly. For example, Hunt et al and Simon et al found that the metabolic capacity of CYP3A and CYP1A2 was preserved in older healthy subjects.^19,20

Donor age is another important factor that could potentially influence the posttransplantation activities of CYP enzymes. Carcillo et al reported that for OLTx recipients with stable liver function, the relationship between the debrisoquin recovery ratio and CYP2D6 mRNA concentration in peripheral blood mononuclear cells, a measure of extrahepatic CYP2D6 expression, was similar to the relationship observed in healthy subjects.¹⁵ Moneketalreported thatan extensive metabolizer CYP2D6 donor liver was given to a poor metabolizer recipient who remained phenotypically a poor metabolizer.²¹ Even when an extensive metabolizer donor liver was matched to an extensive metabolizer recipient, 4 of 40 subjects were found to be phenotypic poor metabolizers. These findings suggest that a balance of hepatic and extrahepatic metabolism exists to determine the overall in vivo metabolic activity of CYP2D6 after liver transplantation, and the donor organs may not be the primary determinant of the overall enzyme activity of the liver in a transplant patient.

Many factors could contribute to the functional change in CYP enzymes after OLTx. The process of liver transplantation may affect enzyme function through organ preservation (cold ischemia time), reperfusion injury, inflammatory changes during or after the surgical procedure, and the immunologic response, which might impair the liver directly or through the involvement of cytokines elaborated during or after the surgical procedure. Many studies suggested that cytokines play an important role in the regulation of mRNA expression or activity of CYP enzymes. Proinflammatory cytokines, such as the interferons, IL-1, IL-6, tumor necrosis factor–, and transforming growth factor–ß have been shown to downregulate the biotransforming capacity of CYP enzymes in cultured hepatocytes or in vivo animal and human studies.^22-25 While the time course of elaboration of these cytokines locally after OLTx is unclear, they could contribute to the depression of CYP-mediated drug metabolism in the months following the transplant procedure.

Other studies have also demonstrated the induction of CYP enzymes by certain cytokines.^26,27 The activity of CYP2E1, as measured by the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio at 4 hours, was markedly induced within 30 days after liver transplantation in both young OLTx patients and older OLTx patients. After 30 days postoperatively, the ratio in young OLTx patients remained at a high level. Our earlier report,⁷ which used the same patient population, did not differentiate between the young and older OLTx patients. Our observation of elevated CYP2E1 function early after OLTx was supported by the subsequent study of Park et al.²⁸ They reported that enhanced formation of NAPQI, a hepatotoxic metabolite of acetaminophen produced by CYP2E1, was observed in the first 10 days after liver transplantation. A possible explanation for the elevated activity of CYP2E1 could be cytokine-mediated induction. Abdel-Razzak et al found that in human hepatocyte cultures, CYP2E1 was the only CYP isoenzyme in which the expression of its mRNA was increased in the presence of IL-4.²⁶ Tindberg et al also reported that in rat brain cortical glial cell cultures, CYP2E1 mRNA increased with application of IL-1ß.²⁷

CYP2C19 activity was markedly reduced within 30 days after OLTx for both young OLTx patients and older OLTx patients. After 30 days postoperatively, the metabolite recovery in young OLTx patients remained lower than the young healthy subjects, while the older OLTx patients had CYP2C19 activity in that time period that was similar to the healthy controls. The result is consistent with the hypothesis that CYP activity would be temporarily impaired due to factors related to liver transplantation (eg, cytokines, organ reperfusion).

The activity of CYP2D6 capacity as estimated by the debrisoquine recovery ratio was reduced after 30 days postoperatively in the older OLTx patients group compared with either young healthy subjects or elderly controls. CYP2D6 activity may also be reduced in young OLTx patients but not to the extent of the older OLTx patients. Bendriss et al measured CYP2D6 activity by the debrisoquine recovery ratio in 9 liver transplant patients followed for up to 3 years after liver transplantation and found it to be stable over time.²⁹ Our observation suggests that some factor alters the debrisoquine recovery ratio long term in OLTx patients and that older OLTx patients may be sensitive to this effect. Further study is needed to evaluate CYP2D6 activity after prolonged survival in OLTx patients.

The only significant difference in the dapsone metabolic ratio was found in the young OLTx patients group in which the ratio was significantly reduced in the first month after OLTx. However, recent studies have suggested that dapsone is not a good probe to measure CYP3A activity since the process of N-hydroxylation of dapsone involves contributions from multiple CYP enzymes.³⁰ Other studies have also suggested that many probes for CYP3A activity do not accurately predict therapy with CYP3A4-metabolized drugs.^31,32

For the other 5 CYP enzymes, young and older OLTx patients experienced similar changes for the metabolic capacity of the CYP450 enzymes after liver transplantation. Donor ages between young and older OLTx patients were balanced. The results of this study indicate that older patients exhibit changes in CYP activity following OLTx that are similar to those observed in young patients.

Prospective studies evaluating the appropriate dosage for drugs that are substrates of CYP2E1, CYP2C19, and CYP2D6 should be conducted in OLTx patients. Drugs that are substrates for CYP2D6 are of particular concern since CYP2D6 activity in the early postoperative period decreased with time following OLTx. These changes in prospective studies should be assessed in relation to current knowledge of the pharmacogenetic differences in expression of these enzyme activities in donor and recipient.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Markedly elevated CYP2E1 capacity, as measured by chlorzoxazone hydroxylation, is observed within 30 days after liver transplantation for both young and older OLTx patients, and the effect is prolonged beyond 30 days posttransplantation in the young OLTx patients. CYP2C19 metabolizing function, as measured by mephenytoin hydroxylation, is significantly reduced during 30 days after liver transplantation. CYP2D6 capacity is impaired after 30 days postoperatively in older OLTx patients. Young and older OLTx patients experienced similar changes after liver transplantation in their metabolic capacity of the major CYP450 enzymes. The administration of drugs that are substrates for these enzymes should be performed cautiously in OLTx patients.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
The authors would like to gratefully acknowledge the assistance of Ms Terry McKaveney and Dr Patrick Kelly in patient recruitment and data collection, Ms Rose Hammond and Dr C. Rosenberg for their assistance in recruiting the geriatric control subjects, and finally to Dr Thomas Starzl who is the inspiration for all of our studies in liver transplantation.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 

1. Venkatakrishnan K, Von Moltke LL, Greenblatt DJ. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J Clin Pharmacol. 2001;41: 1149-1179.[Abstract]

2. Lewis DF. 57 varieties: the human cytochromes P450. Pharmacogenomics. 2004;5: 305-318.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Chang GW, Kam PC. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia. 1999;54(1): 42-50.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

4. Thorn M, Lundgren S, Herlenius G, Ericzon BG, Loof L, Rane A. Gene expression of cytochromes P(450) in liver transplants over time. Eur J Clin Pharmacol. 2004;60: 413-420.[Medline] [Order article via Infotrieve]

5. Mehta MU, Venkataramanan R, Burckart GJ, et al. Antipyrine kinetics in liver disease and liver transplantation. Clin Pharmacol Ther. 1986;39: 372-377.[Medline] [Order article via Infotrieve]

6. Frye RF, Matzke GR, Adedoyin A, Porter JA, Branch RA. Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther. 1997;62: 365-376.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Burckart GJ, Frye RF, Kelly P, et al.: Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation. Clin Pharmacol Ther. 1998;63: 296-302.[CrossRef][Medline] [Order article via Infotrieve]

8. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1): 31-41.[Web of Science][Medline] [Order article via Infotrieve]

9. Frye RF, Stiff DD, Branch RA. A sensitive method for the simultaneous determination of caffeine and its dimethylxanthine metabolites in human plasma: application to CYP1A2 phenotyping. J Liq Chrom Rel Tech. 1998;21: 1161-1171.

10. Frye RF, Stiff DD. Determination of chlorzoxazone and 6-hydroxychlorzoxazone in human plasma and urine by high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1996;686: 291-296.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. May DG, Porter JA, Uetrecht JP, Wilkinson GR, Branch RA. The contribution of N-hydroxylation and acetylation to dapsone pharmacokinetics in normal subjects. Clin Pharmacol Ther. 1990;48: 619-627.[Web of Science][Medline] [Order article via Infotrieve]

12. Frye RF, Branch RA. Improved high-performance liquid chromatographic determination of debrisoquine and 4-hydroxydebrisoquine in human urine following direct injection. J Chromatogr B Biomed Appl. 1996;677: 178-182.[CrossRef][Medline] [Order article via Infotrieve]

13. Moreno JM, Cuervas-Mons V, Rubio E, et al. Chronic renal dysfunction after liver transplantation in adult patients: prevalence, risk factors, and impact on mortality. Transplant Proc. 2003;35: 1907-1908.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Facciuto M, Heidt D, Guarrera J, et al. Retransplantation for late liver graft failure: predictors of mortality. Liver Transpl. 2000;6: 174-179.[Web of Science][Medline] [Order article via Infotrieve]

15. Carcillo JA, Adedoyin A, Burckart GJ, et al. Coordinated intrahepatic and extrahepatic regulation of cytochrome p4502D6 in healthy subjects and in patients after liver transplantation. Clin Pharmacol Ther. 2003;73: 456-467.[Medline] [Order article via Infotrieve]

16. Bjoro K, Hockerstedt K, Ericzon BG, et al. Liver transplantation in patients over 60 years of age. Transpl Int. 2000;13(Suppl 1): S165-170.

17. Geokas MC, Haverback BJ. The aging gastrointestinal tract. Am J Surg. 1969;117: 881-892.[CrossRef][Medline] [Order article via Infotrieve]

18. Greenblatt DJ, Abernethy DR, Shader RI. Pharmacokinetic aspects of drug therapy in the elderly. Ther Drug Monit. 1986;8: 249-255.[Medline] [Order article via Infotrieve]

19. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44: 275-283.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Simon T, Becquemont L, Hamon B, et al. Variability of cytochrome P450 1A2 activity over time in young and elderly healthy volunteers. Br J Clin Pharmacol. 2001;52: 601-604.[Medline] [Order article via Infotrieve]

21. Monek O, Paintaud G, Bechtel Y, Miguet JP, Mantion G, Bechtel PR. Influence of donor and recipient genotypes on CYP2D6 phenotype after liver transplantation: a study of mutations CYP2D6*3 and CYP2D6*4. Eur J Clin Pharmacol. 1998;54: 47-52.[Medline] [Order article via Infotrieve]

22. Pan J, Xiang Q, Ball S. Use of a novel real-time quantitative reverse transcription-polymerase chain reaction method to study the effects of cytokines on cytochrome P450 mRNA expression in mouse liver. Drug Metab Dispos. 2000;28: 709-713.[Abstract/Free Full Text]

23. Carcillo JA, Doughty L, Kofos D, et al. Cytochrome P450 mediated-drug metabolism is reduced in children with sepsis-induced multiple organ failure. IntensiveCareMed. 2003;29: 980-984.

24. Tinel M, Elkahwaji J, Robin MA, et al. Interleukin-2 overexpresses c-myc and down-regulates cytochrome P-450 in rat hepatocytes. J Pharmacol Exp Ther. 1999;289: 649-655.[Abstract/Free Full Text]

25. Frye RF, Schneider VM, Frye CS, Feldman AM. Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure. J Card Fail. 2002;8: 315-319.[CrossRef][Medline] [Order article via Infotrieve]

26. Abdel-Razzak Z, Loyer P, Fautrel A, et al. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol. 1993;44: 707-715.[Abstract]

27. Tindberg N, Baldwin HA, Cross AJ, Ingelman-Sundberg M. Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury. Mol Pharmacol. 1996;50: 1065-1072.[Abstract]

28. Park JM, Lin YS, Calamia JC, et al. Transiently altered acetaminophen metabolism after liver transplantation. Clin Pharmacol Ther. 2003;73: 545-553.[Medline] [Order article via Infotrieve]

29. Bendriss A, Bechtel Y, Paintaud G, et al. Stability of debrisoquine (CYP2D6) phenotype in liver transplant patients. Ther Drug Monit. 1995;17: 113-119.[Medline] [Order article via Infotrieve]

30. Gill HJ, Tingle MD, Park BK. N-hydroxylation of dapsone by multiple enzymes of cytochrome P450: implications for inhibition of haemotoxicity. Br J Clin Pharmacol. 1995;40: 531-538.[Medline] [Order article via Infotrieve]

31. Stein CM, Kinirons MT, Pincus T, Wilkinson GR, Wood AJ. Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with rheumatoid arthritis receiving cyclosporine. Clin Pharmacol Ther. 1996;59: 47-51.[CrossRef][Medline] [Order article via Infotrieve]

32. Gass RJ, Gal J, Fogle PW, Detmar-Hanna D, Gerber JG. Neither dapsone hydroxylation nor cortisol 6beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors. Eur J Clin Pharmacol. 1998;54: 741-747.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Liu, S. Articles by Burckart, G. J. Search for Related Content PubMed PubMed Citation Articles by Liu, S. Articles by Burckart, G. J. Social Bookmarking                   What's this?