Stability of Debrisoquine (CYP2D6) Phenotype in Liver Transplant Patients

Bendriss, Abdenbi; Bechtel, Y; Paintaud, Gilles; Bendriss, El-khalil; Joanne, Christiane; Bresson‐Hadni, Solange; Magnette, J.; Becker, Malte; Gillet, M; Mantion, Georges; Miguet, J.P.; Bechtel, P

doi:10.1097/00007691-199504000-00002

Cited by 9 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with the data by Bendriss et al. , who found no change in CYP2D6 PM phenotype after LT [22]. Moreover, Carcillo et al.…”

Section: Discussionsupporting

confidence: 92%

“…As in our study population, the donor genotype, and therefore the liver genotype, does not play a role in fibrosis, it can be argued that the fibrosis development is not caused by poorly metabolized substrates by the liver itself. This is consistent with the data by Bendriss et al, who found no change in CYP2D6 PM phenotype after LT [22]. Moreover, Carcillo et al showed that the transcriptional regulation of intrahepatic and extrahepatic CYP2D6 mRNA (from peripheral blood mononuclear cells) after LT is coordinated, possibly through a mechanism that is predominantly extrahepatic [23].…”

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

Zimmermann¹,

Hoppe‐Lotichius

Körner³

et al. 2011

Transplant International

View full text Add to dashboard Cite

Summary CYP2D6 is part of the cytochrome P450 system, which catalyzes biotransformation of endogenous substrates and xenobiotics. Approximately 10% of the Caucasian population has two null alleles, resulting in a poor metabolizer (PM) status. Mostly, allele four (CYP2D6*4) is responsible for the PM status, which is suspected to be associated with an accelerated fibrosis progression (FP). The aim of the present study was to analyze the role of the CYP2D6*4 genotype for FP after liver transplantation (LT). Genotypes were determined in liver biopsies (donor) and peripheral blood (recipient) by fluorescence resonance energy transfer. Data were correlated with clinical variables and risk factors for fibrosis. We analyzed 517 LTs performed between 1997 and 2009. Overall donor and recipient allele frequencies were comparable (18.0%, 20.5%; P = 0.43). The donor genotype did not correlate with FP. In contrast, recipients carrying CYP2D6*4, showed a significant higher risk for an accelerated FP (P = 0.011) in HCV positive (P = 0.038) and HCV negative patients (P = 0.033). Results were confirmed by multivariate analysis (Hazard ratio 1.65; P = 0.001). The CYP2D6*4‐associated PM status of the donor liver seems to have no influence on FP after LT. Recipients, carrying the allele, have an elevated risk for an accelerated FP.

show abstract

“…This is consistent with the data by Bendriss et al. , who found no change in CYP2D6 PM phenotype after LT [22]. Moreover, Carcillo et al.…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

Zimmermann¹,

Hoppe‐Lotichius

Körner³

et al. 2011

Transplant International

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionsupporting

confidence: 57%

“…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.…”

Section: Discussionmentioning

confidence: 64%

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

Liu

Frye

Branch

et al. 2005

The Journal of Clinical Pharma

View full text Add to dashboard Cite

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.

show abstract

“…Other commonly studied isozymes of the CYP family are either depressed or unaltered during the early postoperative period. [23][24] The practical application of this study to liver transplant patients is that increased metabolic degradation of administered drugs that are metabolized by CYP2E1 may lead to either a diminished effect of the agent or to increased drug toxicity from a metabolite. Several of the fluorinated anesthetic agents, such as enflurane and sevoflurane, are metabolized by CYP2E1, and some dosage alteration may be necessary in a liver transplant patient who requires additional surgery in the early posttransplant period.…”

mentioning

confidence: 99%

Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation*

Burckart

Frye

Kelly

et al. 1998

Clin Pharmacol Ther

View full text Add to dashboard Cite

Objective-To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation.Methods-Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods.Results-The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean ± SD, 6.4 ± 5.1) was significantly higher than that after 1 month after surgery (2.1 ± 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 ± 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 ± 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 ± 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 ± 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups.Conclusions-We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after sugery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.Alterations in drug absorption, distribution, metabolism, and urinary and biliary excretion have been documented at various times after organ transplantation. 1 Drug metabolism in liver transplant patients is of particular concern because the liver is primarily responsible for the biotransformation of most xenobiotics. The procedure of transplanting a complete or partial liver from a donor to the recipient involves a number of steps that ultimately affect drug metabolism. The process of preservation, reperfusion injury, inflammatory changes associated with the surgical procedure, technical complications involving the flow of blood and bile, and the immunologic response of the recipient all produce complex effects that primarily ...

show abstract

Stability of Debrisoquine (CYP2D6) Phenotype in Liver Transplant Patients

Cited by 9 publications

References 0 publications

The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

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

Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation*

Contact Info

Product

Resources

About