Effect of enzyme induction on Sandimmun® (cyclosporin A) biotransformation and hepatotoxicity in cultured rat hepatocytes and in vivo

Bouis, Patrick; Brouillard, J.-F.; Fischer, Volker; Donatsch, P.; Boelsterli, Urs A.

doi:10.1016/0006-2952(90)90024-f

Cited by 17 publications

(5 citation statements)

References 22 publications

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“…In comparison with previous studies of in vitro CyA biotransformation (Bouis et al 1990;Pichard et al 1990Pichard et al , 1996Ferrini et al 1997), our cultures exhibited an overall increase in metabolic output. In contrast to methods described elsewhere in which a Percoll Õ purification stage results in cell populations with approximately only 1% non-parenchymal cells (Dunn et al 1989), our methods result in the establishment of a sandwich culture with approximately 20-30% non-parenchymal cells.…”

Section: Discussionsupporting

confidence: 56%

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Biotransformation of cyclosporin in primary rat, porcine and human liver cell co-cultures

Schmelzer¹,

Acikgoez²,

Frühauf³

et al. 2006

Xenobiotica

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The purpose of this study was to investigate the species-specific cyclosporin biotransformation in primary rat, human, and porcine liver cell cultures, and to investigate the suitability of a modified sandwich culture technique with non-purified liver cell co-cultures for drug metabolism studies. A sandwich culture was found to enhance hepatocellular metabolic activity and improve cellular morphology and ultrastructure. The cyclosporin metabolites AM9 and AM1 were formed in porcine and human liver cell sandwich co-cultures at levels corresponding to the respective in vivo situations. In contrast, metabolite profiles in rat hepatocytes were at variance with the in vivo situation. However, for all cell types, the overall metabolic activity was positively influenced by sandwich co-culture. The initial levels of albumin synthesis were higher in sandwich cultures than in those without matrix overlay. It is hypothesized that the sandwich culture system provides an improved microenvironment and is, therefore, an advantageous tool for in vitro studies of drug metabolism.

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Section: Discussionsupporting

confidence: 56%

“…This is, at least in part, a consequence of the sandwich co-culture configuration used. Previous studies (Bouis et al 1990) have been concerned with earlier culture stages, since the culture configuration used was not able to provide stable metabolism over longer periods.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of cyclosporin in primary rat, porcine and human liver cell co-cultures

Schmelzer¹,

Acikgoez²,

Frühauf³

et al. 2006

Xenobiotica

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“…CSA undergoes extensive hepatic metabolism by cytochrome P‐450 enzymes, mainly CYP3A4 [11, 12, 14] and is also a substrate for P‐gp [18–20]. Although more than 80% of CSA metabolism is attributed to CYP3A4 [14], CYP3A5 has also been shown to metabolize CSA [16], and there is some evidence that the formation of cyclic metabolites (AM1c, AM1c9) may be mediated by 3‐methylcholanthrene‐inducible CYP isoforms such as CYP1A1 or CYP1A2 [15, 17]. Furthermore, the effects observed with different preparations of SJW may vary greatly, depending on the composition of the individual plant extract.…”

Section: Discussionmentioning

confidence: 99%

“…These are subject to further biotransformation yielding AM1c (cyclized AM1) and AM19 (hydroxylated at amino acids 1 and 9) as the quantitatively most important secondary metabolites [12]. The main enzyme in CSA metabolism is CYP3A4 [14], but other isoforms may be involved [15–17]. CSA is also a substrate for the MDR1‐transporter P‐glycoprotein (P‐gp) [18–20].…”

Section: Introductionmentioning

confidence: 99%

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients

Bauer

Störmer

Johne

et al. 2003

Brit J Clinical Pharma

166

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Aim This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA).Methods In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. at baseline to 4.2 mg day -1 kg -1 at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and C max values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. Conclusion Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.

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“…Cytochrome P-450 enzymes (CYP) are responsible for the metabolism of cyclosporine, with CYP3A4 being the predominant enzyme involved in humans (Aoyama et al, 1989;Combalbert et al, 1989;Bouis et al, 1990;Sewing et al, 1990). Potential inhibitors of CYP in humans include erythromycin, ketoconazole, miconazole, diltiazem, progesterone, cortisol, prednisone, prednisolone, and methylprednisolone while grapefruit juice and ketoconazole have been shown to inhibit CsA metabolism in dogs (Pichard et al, 1990;Dahlinger et al, 1998;Bauer et al, 2003;Amatori et al, 2004Radwanski et al, 2011.…”

mentioning

confidence: 99%

Evaluation of the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs after a single dose and at steady‐state

Pieper

Dirikolu

Campbell

et al. 2016

Vet Pharm & Therapeutics

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The aim of the study was to describe the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs when investigated as a single dose and at steady-state. Five healthy adult dogs were used in the study in a crossover design receiving either 5 mg/kg of cyclosporin A (CsA) alone or 5 mg/kg of fluconazole with 2.5 mg/kg of cyclosporin A (CsA/Flu) for 35 days. Pharmacokinetic curves were performed on day 1 and day 35 in addition to sampling trough and suspected peak concentrations (C2) twice weekly with LC/MS/MS. There was no statistically significant difference noted in any pharmacokinetic value (AUC [day 1, P = 0.225], AUC [day 35, P = 0.225], t [day 1, P = 0.279; day 35, P = 0.686], and C [day 1, P = 0.225; day 35, P = 0.225]) between the treatment groups by sampling day. There was a statistically significant increase in AUC (CsA P = 0.043; CsA/Flu P = 0.043) and t (CsA P = 0.042, CsA/Flu P = 0.042) over time within each group There were no significant differences in the C (CsA P = 0.08; CsA/Flu P = 0.08) when comparing day 1 vs. day 35. Steady-state cyclosporine concentrations were achieved by day 10 in both groups. Subjectively, individual variability was noted among the dogs and a much larger sample size would be beneficial in a future study.

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Effect of enzyme induction on Sandimmun® (cyclosporin A) biotransformation and hepatotoxicity in cultured rat hepatocytes and in vivo

Cited by 17 publications

References 22 publications

Biotransformation of cyclosporin in primary rat, porcine and human liver cell co-cultures

Biotransformation of cyclosporin in primary rat, porcine and human liver cell co-cultures

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients

Evaluation of the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs after a single dose and at steady‐state

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