Metabolism Of Cyclosporine Research Articles

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Effect of Liver Regeneration on the Pharmacokinetics of Immunosuppressive Drugs

In liver transplantation the graft has been known to undergo regeneration, which is associated with down-regulation of the cytochrome P450 system. The latter is involved in the metabolism of several immunosuppressive drugs. The aim of this study was to investigate the effect of liver regeneration on the pharmacokinetics (PK) of cyclosporine, rapamycin, and tacrolimus. Rats were subjected to either partial hepatectomy (PH) or sham operation (SH). Cyclosporine, rapamycin, and tacrolimus PK studies were performed at 0, 24, and 96 hours postoperatively. The areas under the curve (AUC), trough levels, and maximum concentrations (Cmax) for cyclosporine and tacrolimus were numerically higher in the animals subjected to PH. The PK studies of rapamycin were not affected by PH. These studies indicated that cyclosporine and tacrolimus metabolism may be inhibited during liver regeneration.

CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients

Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight (P < 0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.

CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine

The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6+/-3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29-0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.

No Kinetic Interaction Between Levetiracetam and Cyclosporine: A Case Report

Levetiracetam is a new antiepileptic drug reported to be effective and well-tolerated in adults and children affected by epilepsy. Its lack of hepatic cytochrome metabolism is the theoretic basis for the absence of interactions with other drugs that follow this pathway. We present a 14-year-old girl who underwent orthotopic heart transplantation, followed by antirejection therapy including cyclosporine. Symptomatic occipital lobe epilepsy developed that was successfully treated with oxcarbazepine, but cyclosporine plasma levels decreased to below the antirejection threshold. Oxcarbazepine was replaced by levetiracetam. Levetiracetam did not affect the metabolism of cyclosporine, and cyclosporine plasma levels have remained in the therapeutic range up to now. The patient is still seizure-free and does not complain of any side effects after a 1-year follow-up. Further studies are necessary to confirm the lack of interactions between these drugs, which would make levetiracetam a useful therapeutic option in managing seizure control during antirejection therapy with cyclosporine.

Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR–RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4 mg kg−1). The plasma concentrations of cyclosporine were measured for up to 24 h post dose by high-performance liquid chromatography–electrospray mass spectrometry. We found that the mean Cmax (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng ml−1 (*18B/*18B) (p = 0.037) and the mean AUC0-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml-1 h (*18B/*18B) (p = 0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, Tmax exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2 h post dose compared with *1/*18B (p = 0.062) or *1/*1 (p = 0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p > 0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.

Effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors

The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined. The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial. For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25-45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.

Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients

To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR-ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose-adjusted trough concentrations and metabolic ratio (MR) values were calculated. The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1*3). However, no significant difference was found for the dose-adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92+/-0.62 for CYP3A5*3/ *3 (n=14), 0.99+/-0.51 for CYP3A5*1/*3 (n=15), and 1.45+/-0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites.

Evaluation of Microsomal Incubation Conditions on CYP3A4-Mediated Metabolism of Cyclosporine A by a Statistical Experimental Design

The effect of changes in microsomal incubation conditions (NADPH, Mg(2+), Cl(-), NADPH-regenerating system and pH) on the formation of the CYP3A4 metabolites AM1 and AM9 from CsA were studied by application of a fractional factorial design. Metabolism was studied in microsomes of transfected human liver epithelial (THLE) cells specifically expressing CYP3A4. Within the conditions tested, a 3-4-fold difference in formation of CsA metabolites was observed. Formation of both AM1 and AM9 was favoured by a low Mg(2+) concentration (0.5 mM) and no addition of Cl(-) to the incubation matrix. However, while a high NADPH concentration (1.75 mM) was the single most important factor for the formation of AM1, changes in NADPH concentration between 0.25 and 1.75 mM had no influence on AM9 formation. Formation of the two metabolites also differed in their influence by pH changes, as a change in pH from 7.2 to 7.5 significantly increased the formation of AM9, while formation of AM1 was unaffected by this change. The present study showed that relatively small changes in the incubation matrix had a significant influence on the microsomal CYP3A4-mediated metabolism of CsA. Systematic studies on microsomal incubation conditions could be a key to improve metabolic in vitro-in vivo extrapolations in drug development.

Th-P15:217 Bidirectional flux of cholesterol between cells and serum

In this work we have investigated a system of long-term primary cultures of adult human hepatocytes which, in contrast to those previously described, has the advantage of requiring neither the use of additive cells as in co-cultures, nor of matrix component preparations like Matrigel or collagen sandwich. This system has been used previously for long-term cultures of hepatocytes from young baboon, and some modifications have been introduced here to take into account the specificity of adult human hepatocytes. In this system, hepatocytes are plated at confluence on collagen-coated dishes and cultured in a serum-free medium consisting of Williams'E supplemented with hormones and growth factors. Proteins secreted specifically by the liver, including albumin, α-1 antitrypsin, plasminogen, fibrinogen, lipoproteins ApoA1 and ApoB100, have been quantified in the extracellular medium as a function of time, either by immunoblot or ELISA. In addition, the expression and inducibility of CYP proteins of the CYP1, CYP2 and CYP3 families in response to their prototypical inducers including 2,3,7,8-tetrachlorodibenzo(p)dioxin and rifampicin, have been evaluated by immunoblot analysis of microsomes or cell lysates. Moreover, the oxidative metabolism of cyclosporin A, a monoxygenase activity depending on CYP3A4, has been monitored directly on the cultured cells by HPLC analysis of extracellular medium. Our results show that, under these culture conditions, adult human hepatocytes retain these phenotypical characteristics for at least 35 days. This system meets the requirements for use as a model for screening CYP protein inducers.

Concomitant Cyclosporine and Micafungin Pharmacokinetics in Healthy Volunteers

Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645+/-236 mL/h/kg, 546+/-101 mL/h/kg (P = .01), and 540+/-104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.

Altered Cytochrome P450 Metabolism of Calcineurin Inhibitors: Case Report and Review of the Literature

A 19-year-old woman was admitted to receive a kidney transplant from a nonliving donor. At the time of transplantation, she was taking oral phenytoin 300 mg every morning, 100 mg at noon, and 300 mg every evening (total of 700 mg/day) to treat seizures secondary to hemodialysis. Immediately after the transplantation, phenytoin treatment was resumed, and immunosuppressive therapy consisting of antithymocyte globulin, cyclosporine, mycophenolate mofetil, and corticosteroids was started. Her cyclosporine blood levels varied over the first 10 days after transplantation. Cyclosporine was discontinued, and tacrolimus was begun after acute rejection was discovered. The rejection was treated with antithymocyte globulin, plasmapheresis, and intravenous immunoglobulin, and subsequently resolved; however, the patient's blood concentrations of tacrolimus varied widely. Phenytoin is an antiepileptic drug that induces hepatic enzymes, affecting the cytochrome P450 3A family. These enzymes metabolize approximately 50% of all prescribed drugs, including cyclosporine and tacrolimus. According to the Naranjo adverse drug reaction probability scale, this patient's adverse drug reaction probably occurred from altered metabolism of cyclosporine and tacrolimus due to phenytoin therapy. Clinicians must identify drug interactions between metabolic enzyme inducers or inhibitors and drug substrates with narrow therapeutic ranges, closely monitor drug concentrations, and observe patients for clinical signs and symptoms of therapeutic failure or toxicity. In daily practice, clinicians should explore the metabolic characteristics of drugs and their biotransformation pathways to identify patients who require alternative therapy.

The CAM network – Challenges and opportunities

Over the past two decades, there has been an increase in both interest in and use of complementary and alternative medicine (CAM) among patients in the developed world. This has been best documented among adult patients, but it is increasingly clear that CAM is more widely used by families for the treatment of children, especially children with chronic diseases. The frequency of CAM use among children with some chronic disorders approaches 70%. The increase in interest in CAM is related to a number of factors: cultural belief in the use of traditional medicines, the assumption that natural therapies are more likely to be safe, and the unfortunate fact that our ability to control many chronic diseases and the adverse effects of conventional therapy is less than optimal. This presents a problem for the child health care practitioner. First, many parents are reluctant to disclose to the practitioner that they are using CAM for fear of damaging the doctor-patient relationship or of being labelled a CAM user. Second, even when families do disclose the use of CAM, the child health care worker is often faced with a paucity of reliable information on the efficacy and safety of these preparations, notably when used in combination with conventional medications. This is unfortunate for all concerned because there is increasing evidence that CAM may be more efficacious, but also less safe, than was previously believed. As an example, we now know that St John’s wort is a moderately effective agent in the treatment of moderate depression. It is also known that St John’s wort is a modestly effective inhibitor of CYP3A4, the isozyme of the cytochrome responsible for 50% of human drug metabolism via cytochrome P450, including the metabolism of cyclosporine, nifedipine and nelfinavir. An additional example is the fact that many therapeutic products (ranging from antibiotics to immunosuppressives) originated from natural products. Teaching about CAM in the undergraduate and postgraduate medical curriculum of most conventional practitioners ranges from scant to none. Thus, the child health care practitioner is faced with a major knowledge gap in terms of providing optimal therapy for children and their families. In this context, the development of PedCAM, a childfocused CAM Network, is a welcome development. What is the promise of such a network? First, it provides an opportunity for clinicians and researchers with an interest in CAM to interact on a regular basis with people with similar interests. This includes the opportunity to collaborate with international partners. The development of National Institutes of Health-supported research units in the United States and international groups such as the Consortium for the Globalization of Chinese Medicine suggests that there is rich potential in such collaborations. This leads to the second opportunity, which is the development of research projects to assess the safety, efficacy and optimal use of CAM to help guide practitioners to use the right therapy for the right patient. The third opportunity is the dissemination of validated evidence-based information about the appropriate use

Atorvastatin does not affect the pharmacokinetics of cyclosporine in renal transplant recipients

The aim of the present study was to evaluate the possible influence of atorvastatin on the pharmacokinetics of cyclosporine (INN ciclosporin) and its main metabolites, AM1 and AM9, in renal transplant recipients. Whole blood samples from 18 renal transplanted patients on cyclosporine-based immunosuppressive therapy were collected prior to and after 4 weeks of treatment with atorvastatin (10 mg/day) and analysed with regard to both cyclosporine and its main metabolites, AM1 and AM9, using a specific chromatographic method with ultraviolet detection. On average, AUC(0-12) [area under the whole blood concentration versus time curve in the dosing interval (0-12 h)] of cyclosporine was 5% (-16, 5) (90% confidence interval) lower upon co-administration with atorvastatin. No statistically significant changes in any of the calculated pharmacokinetic variables [AUC(0-12), maximum whole blood concentration (C(max)), whole blood concentration 12 h post dose (C(12)), time to C(max) (t(max)), terminal half-life (t(1/2))] for cyclosporine or the two metabolites, AM1 and AM9, upon atorvastatin treatment were observed. On average, atorvastatin did not affect the ratio between the CYP3A4-mediated metabolite AM9 and cyclosporine, suggesting that atorvastatin does not affect the CYP3A4 metabolism of cyclosporine to any significant extent. However, the influence of atorvastatin on the ratio between AM9 and cyclosporine showed large interindividual variability. The results of this study indicate that atorvastatin does not, on average, affect cyclosporine pharmacokinetics in renal transplant recipients.

Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine

Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H-cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple-dose, open-label clinical study of 12 healthy volunteers. Subjects received a 200-mg intravenous loading dose of anidulafungin, followed by a daily 100-mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose-limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus

Objective CYP3A is the major enzyme responsible for metabolism of the calcineurin inhibitors cyclosporine (CsA) and tacrolimus. Our objective was to determine the relationship between genetic polymorphisms of CYP3A5 with respect to interindividual variability in CsA and tacrolimus pharmacokinetics. Methods Kidney transplant recipients receiving CsA (n = 137) or tacrolimus (n = 30) were genotyped for CYP3A5*3 and *6 by a PCR/RFLP method. The patients were grouped according to the CYP3A5 genotype. Dose-adjusted trough levels were correlated with the corresponding genotype. Results At 3, 6, and 12 months, the tacrolimus dose-adjusted trough levels (dose-adjusted C0) showed a statistically significant difference between the group of CYP3A5*3/*3 (n = 19) and the group of CYP3A5*1 allele carriers. The former was higher than the latter. The CsA dose–adjusted C0 and the actual C0 did not display a significant relation ( P < .05) between the group of CYP3A5*3/*3 and the group of CYP3A5*1 allele carriers. Conclusion Patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target concentrations compared to those with the CYP3A5*1 allele.

Characterization of a Phase 1 Metabolite of Mycophenolic Acid Produced by CYP3A4/5

To characterize a phase 1 metabolite of mycophenolic acid (MPA) and the human cytochrome P450 isoform(s) (CYP) involved in its formation. MPA metabolites were investigated in blood and urine samples from transplant patients under mycophenolate mofetil therapy (n = 5) as well as with in vitro incubation of MPA with human liver microsomes. The CYP isoforms involved in the oxidative metabolism were investigated in vitro on human liver microsomes with isoform-specific inhibitors as well as in human embryonic kidney cell lines expressing recombinant human CYPs. The analytic methods used were based on LC-MS/MS. A 6-O-desmethyl-MPA (DM-MPA) metabolite and 2 related glucuronides were identified in patients' blood and urine. Human liver microsomes produced DM-MPA with an apparent Km = 0.83 +/- 0.06 mmol/L and Vmax = 5.57 +/- 0.29 pmol/mg/min. The CYP3A inhibitor ketoconazole was found to inhibit DM-MPA formation by 50.3% with respect to the control, and trimethoprim (CYP2C8 inhibitor) reduced it by 30.1%. However, DM-MPA was produced only by the transfected cell lines expressing CYP3A4 and, to a lesser extent, CYP3A5. In vitro, MPA at concentrations above the plasma therapeutic range was found to decrease the metabolism of tacrolimus, suggesting a possible competition for CYP3A. No effect of MPAat therapeutic or higher level was found on cyclosporin metabolism. The phase 1 metabolite of MPA previously known as M-3 was identified as 6-O-desmethyl-MPA and is produced by CYP3A4/5 and probably CYP2C8. MPA might compete with other drugs on CYP3A because of its high therapeutic concentrations, although this was not the case for cyclosporin and to only a small extent for tacrolimus.

In vitro metabolism of cyclosporine A by human kidney CYP3A5

The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20 μM CsA) was positively associated with the detection of CYP3A5 protein and presence of the CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active CYP3A5*1-positive renal microsomal preparation yielded an apparent K m (15.5 μM) similar to that of CYP3A5 (11.3 μM). Ketoconazole (200 nM) inhibited renal AM9 formation by 22–55% over a CsA concentration range of 2–45 μM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in CYP3A5*1/*3 livers, compared to CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a CYP3A5*1/*3 genotype, compared to those with a CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type CYP3A5*1 allele.

Interaction Between Sibutramine and Cyclosporine

American Journal of TransplantationVolume 3, Issue 7 p. 906-906 Free Access Interaction Between Sibutramine and Cyclosporine First published: 18 June 2003 https://doi.org/10.1034/j.1600-6143.2003.00159.xCitations: 8AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor: Obesity is common after renal transplantation and is associated with significant decreased patient and graft survival rates (1). A safe and effective pharmacological approach to induce and maintain significant weight loss would therefore be welcomed in affected patients. Sibutramine is a recently released tertiary amine that causes inhibition of neuronal re-uptake of both epinephrine and serotonine at central nervous system sites affecting satiety. Its efficacy to induce and maintain weight loss is demonstrated in nontransplanted patients (2). We report on an obese kidney recipient in whom sibutramine treatment was followed by a significant increase in cyclosporine serum trough level that required a dose reduction of 25%. A 26-year-old woman underwent living-related kidney transplantation in February 1997 for end-stage renal disease secondary to chronic interstitial nephritis. Maintenance therapy included cyclosporine 100 mg b.i.d., azathioprine, prednisolone and amlodipine. Her weight had increased from 49.8 kg at transplantation to 97.8 kg (BMI: 38 kg/m2) in April 2002. Serum creatinine was at that time 79 µmol/dL. As a slimming diet associated with orlistat for 27 months was unsuccessful, sibutramine 10 mg o.d. (Abbott, Ottignies-Louvain-la-Neuve, Belgium) was started on April 18th 2002. On April 25th, the cyclosporine serum trough level (Abbott laboratory, FPIA, AxSYM) level had risen from 79 to 152 ng/mL, requiring reduction of the daily dose of 25 mg (12.5%) from the April 26th (Figure 1). On May 2nd the cyclosporine serum trough level was at 162 ng/mL, justifying a further reduction of the daily dose of 25 mg. Currently, after 10 months of sibutramine treatment, the patient has lost 8.1 kg, and the blood pressure control and creatinine serum concentration remained unchanged. Cyclosporine serum trough levels are stable and similar to those observed before onset of sibutramine treatment, despite a dose reduction of 25%, as compared with pre-sibutramine treatment. Figure 1Open in figure viewerPowerPoint Changes in cyclosporine serum trough level (◆) and cyclosporine dose (□) in relation to sibutramine therapy 10 mg o.d. Both the sharp increase in cyclosporine trough level following sibutramine introduction, without other clinical or pharmacological modifications, and the persistent reduced need in cyclosporine during sibutramine therapy strongly suggest the existence of a competitive interaction between sibutramine and cyclosporine metabolism. Such interaction was not unexpected as sibutramine is demethylized into its metabolites at the cytochrome P450 3A4 level, the site also affecting cyclosporine metabolism (3). As illustrated in this case, sibutramine could become a useful adjunct to achieve body weight loss in transplanted patients. Our observation strongly suggests the existence of an interaction between sibutramine and cyclosporine. We therefore recommend close monitoring of the cyclosporine serum trough level in such patients, in order to adjust cyclosporine dose and avoid its attendant toxicity. Gaëtan Clerbaux, Eric Goffin and Yves Pirson Université Catholique de Louvain Nephrology Brussels Belgium References 1 Meier-Kriesche H-U, Arndorfer JA and Kaplan B. The impact of body mass index of renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 2002; 73(1): 70– 74.CrossrefPubMedWeb of Science®Google Scholar 2 James WPT, Astrup A, Finer N et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119– 2125.CrossrefCASPubMedWeb of Science®Google Scholar 3 Luque CA, Rey JA. Sibutramine: a serotonin-epinephrine reuptake-inhibitor for the treatment of obesity. Ann Pharmacother 1999; 33: 968– 978.CrossrefCASPubMedWeb of Science®Google Scholar Citing Literature Volume3, Issue7July 2003Pages 906-906 AST and ASTS members - please log in via your Society website for full journal access.AST Members >> ASTS Members >> FiguresReferencesRelatedInformation

Review of the pharmacokinetics, interactions and adverse reactions of cyclosporine in people, dogs and cats

Cyclosporine is being increasingly used in veterinary medicine. Oral formulations of the drug have found many therapeutic uses, but topical formulations have met with only limited success, probably owing to...