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

Lampen, A.; Christians, Uwe; Bader, Augustinus; Hackbarth, Ingelore; Sewing, Karl–Friedrich

doi:10.1159/000139380

Cited by 63 publications

(40 citation statements)

References 17 publications

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“…No clear relationship between sex and CL/F had been previously established for ciclosporin. A sex-dependent racial difference in the disposition of ciclosporin was reported in a small number of healthy patients [35] and in vitro studies have suggested that women clear CYP3A4 substrates more rapidly than men do, which may result in a higher apparent volume of distribution and CL/F [36] , in apparent contradiction with the present results. The influence of this covariate needs to be confirmed as the observed effect could be due to confounding factors.…”

Section: Discussioncontrasting

confidence: 99%

Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients

et al. 2013

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Section: Discussioncontrasting

confidence: 99%

Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients

et al. 2013

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“…Although the blood drug concentrations are well below the associated K m for CYP3A4 (4 -7 M for cyclosporine, tacrolimus, and sirolimus) (Lampen et al, 1995(Lampen et al, , 1996(Lampen et al, , 1998 and P-gp (8 M for cyclosporine) (Saeki et al, 1993), the intracellular concentrations in enterocytes and hepatocytes may be higher, resulting in a transition to nonlinear kinetics for cyclosporine.…”

Section: Discussionmentioning

confidence: 99%

Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Lindh

Andersson²,

Eliasson

et al. 2011

Drug Metab Dispos

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ABSTRACT:The most important enzyme in hepatic drug metabolism is cytochrome P450 3A4. Published in vitro data indicate that vitamin D may up-regulate the expression of the CYP3A4 gene. Individual vitamin D levels are highly dependent on sunlight exposure and show great seasonal variability in northern countries. The aim of the present study was to investigate whether plasma concentrations of CYP3A4 drug substrates exhibit seasonal changes compatible with a stimulatory effect of vitamin D on drug metabolism. Three immunosuppressants (tacrolimus, sirolimus, and cyclosporine) were analyzed, because these CYP3A4 drug substrates are subject to long-term use and repeated concentration determinations. In addition, mycophenolic acid was included in the analysis as a control drug independent of CYP3A4 metabolism. Concentration-to-dose ratios were extracted from the Karolinska Therapeutic Drug Monitoring database and compared between the 3-month periods of lowest and highest vitamin D levels. Sirolimus and tacrolimus levels showed seasonal variability that was highly consistent with changes in vitamin D; for example, significantly lower drug concentrations in July to September than in January to March. As expected, no significant difference was evident for mycophenolic acid, but this result was also the case with cyclosporine, possibly due to cross-reactivity of CYP3A4-mediated metabolites with the immunoassay used for quantification. In conclusion, there is cyclic variation in blood levels of important immunosuppressants throughout the year that correlates with UV light-dependent changes in vitamin D levels. Even though a causal relationship remains to be established, it is suggested that individual differences in vitamin D may contribute to variability in drug metabolism and disposition.

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“…It is well known that the metabolism of cyclosporine and tacrolimus decrease when they are co-administered with drugs that act as substrates and/ or inhibitors for CYP3A4. 8,9) In addition, cyclosporine enhances the plasma concentrations of several drugs such as atorvastatin and repaglinide, which are metabolized by CYP3A4, whereas tacrolimus has no eŠect on atorvastatin pharmacokinetics ( Table 1). [10][11][12][13][14][15][16] However, there are few in vitro studies comparing the eŠects of the immunosuppressants on human hepatic CYP-mediated drug-metabolizing activity under the same experimental conditions.…”

Section: Introductionmentioning

confidence: 99%

Effect of Cyclosporine and Tacrolimus on Cytochrome P450 Activities in Human Liver Microsomes

et al. 2007

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The eŠects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresoruˆn O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4′ -hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6b-hydroxylation activities in human liver microsomes were compared. Cyclosporine and tacrolimus, at concentrations of 0.2 or 2 mM, neither inhibited nor stimulated any of the metabolic activities except for those of CYP3A4. On the other hand, cyclosporine and tacrolimus competitively inhibited CYP3A4-mediated nifedipine oxidation activity, with inhibition constants (K i ) of 1.42 and 0.36 mM, respectively. In addition, 20 mM cyclosporine inhibited CYP2C19 and CYP2D6 activities by 29％ and 30％, respectively. These results suggest that tacrolimus would not cause clinically signiˆcant interactions with other drugs, which are metabolized by CYPs, via the inhibition of hepatic metabolism and that the reason why cyclosporine, but not tacrolimus, has a pharmacokinetic inhibitory eŠect might be that the dosage and/or the unbound concentrations around its metabolic enzymes are higher than those of tacrolimus, rather than the diŠerences in the inhibition potential. Obvious substrate-dependent eŠects on CYP3A4-inhibition potential were not observed.

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

Cited by 63 publications

References 17 publications

Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients

Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients

Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Effect of Cyclosporine and Tacrolimus on Cytochrome P450 Activities in Human Liver Microsomes

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