Cyclosporin metabolism in transplant patients

Christians, Uwe; Sewing, Karl–Friedrich

doi:10.1016/0163-7258(93)90059-m

Cited by 149 publications

(65 citation statements)

References 211 publications

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“…unnatural and D-amino acids) into linear peptides can impart sufficient metabolic stability to facilitate activity after systemic administration , as shown by E-2078, a metabolically stable analogue of dynorphin A-(1-8) which exhibits analgesic activity in humans after intramuscular injection (Fujimoto and Momose, 1995). In contrast, macrocyclic peptides are typically stable to proteases and are instead metabolized by cytochrome P 450 enzymes involved in drug metabolism (Christians and Sewing, 1993;Delaforge et al, 1997). Moreover, their macrocyclic structure often results in intramolecular hydrogen bonding which can facilitate membrane permeability (Rezai et al, 2006), thereby enhancing oral absorption and CNS penetration.…”

Section: Discussionmentioning

confidence: 99%

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

Eans

Ganno

Reilley

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSECyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic k opioid receptor ( CONCLUSIONS AND IMPLICATIONSThe macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. Abbreviations

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Section: Discussionmentioning

confidence: 99%

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

Eans

Ganno

Reilley

et al. 2013

British J Pharmacology

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“…Suppression of CsA metabolism may be associated with a decrease in the CsA parent:parent + metabolite ratio [12,19], and CsA metabolites are reported to be less immunosuppressive and more toxic than the parent com pound [20,21], In addition, ketoconazole has been re ported to have immunosuppressive activity [12,18,22]. For these reasons, we carried out this prospective ran domized study not only to study CsA dose reduction but also to explore the possible additional biological benefits, i.e.…”

Section: Discussionmentioning

confidence: 99%

Coadministration of Ketoconazole to Cyclosporin-Treated Kidney Transplant Recipients: A Prospective Randomized Study

et al. 1995

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In this work, 100 living related donor kidney transplant recipients under cyclosporin (CsA) therapy were randomly distributed to two groups. Group 1 were administered ketoconazole, with group 2 serving as the control. Ketoconazole was given orally, 100 mg/day, while the dose of CsA was adjusted for a CsA whole blood trough level of 100-150 ng/ml. Patients and controls were assessed regularly in an outpatient clinic for 12 months and compared statistically for CsA dose, graft and liver functions, cholesterol, blood sugar, CsA nephrotoxicity, acute rejection episodes, chronic rejection and fungal skin infections. Statistical analysis showed a significant reduction in the CsA dose in the ketoconazole-treated group (73-76%), along with significantly lower alanine aminotransferase, aspartate aminotransferase, bilirubin, and serum creatinine values. CsA chronic nephrotoxicity and chronic rejections were also significantly lower in the ketoconazole-treated group, as was fungal skin infection (6.6 vs 63.2%). From this study, we conclude that addition of a low dose of ketoconazole to CsA-treated kidney transplant recipients not only saves costs, but may also have a favorable effect on graft function, chronic CsA nephrotoxicity, chronic rejection and fungal skin infection.

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“…The molecular ion [M-H]~ and the main fragment at m/z = 1,090 (-residue of amino acid 1 [5]) were included in the analysis. To compare metabolite patterns, concentrations of AMI, AM9, AM 1c, AM4N, AMI A.…”

Section: Identification O F Ciclosporin Metabolitesmentioning

confidence: 99%

“…The undecapeptide ciclosporin (Sandimmun®, Sandoz, Basle, Switzerland) is widely used as an immunosuppressant after organ transplantation [1,2] and for therapy of im mune diseases [3], Ciclosporin is biotrans formed by hepatic cytochrome P450 (CYP) 3A enzymes [4] to more than 30 metabolites [5]. The reactions involved are hydroxylation, déméthylation, oxidation to aldehydes and a carboxylic acid as well as cyclization at amino acid 1.…”

Section: Introductionmentioning

confidence: 99%

Drug Interactions and Interindividual Variability of Ciclosporin Metabolism in the Small Intestine

et al. 1996

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The undecapeptide ciclosporin is used as immunosuppressant after organ transplantation and for therapy of immune diseases. Low and variable bioavailability of ciclosporin has been attributed to its metabolism in the small intestine. The aim of the present study was to investigate drug interactions and interindividual variability of ciclosporin metabolism in the small intestine. Ciclosporin metabolism was studied in vitro using microsomes isolated from the small intestine of humans and pigs. The metabolites generated were quantified by HPLC and identified by mass spectrometry. Using specific antibodies and inhibitors, we showed that, as in the liver, cytochrome P450 3A (CYP 3A) enzymes are responsible for ciclosporin metabolism in the human small intestine. Of the 28 xenobiotics included in the study, 16 drugs, all well-known CYP 3A inhibitors, inhibited ciclosporin metabolism in the small intestine. In the small intestine of different patients, the rate of metabolism varied by a factor of 10. Ciclosporin was metabolized faster by small intestine microsomes from female (n = 4) than from male (n = 10) patients (p < 0.009).

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Cyclosporin metabolism in transplant patients

Cited by 149 publications

References 211 publications

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

Coadministration of Ketoconazole to Cyclosporin-Treated Kidney Transplant Recipients: A Prospective Randomized Study

Drug Interactions and Interindividual Variability of Ciclosporin Metabolism in the Small Intestine

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