The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent*

Kaplan, Bruce; Meier-Kriesche, Herwig Ulf; Napoli, Kimberly L.; Kahan, Barry D.

doi:10.1016/s0009-9236(98)90120-5

Cited by 114 publications

(55 citation statements)

References 15 publications

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“…Furthermore, coadministration of oral cyclosporine with oral sirolimus in healthy volunteers resulted in a 6-fold increase in the C max and a 2.5-fold increase in the area under the concentration verus time curve for sirolimus (Rapamune product information; Wyeth-Ayerst). A similar study performed in stable kidney transplant patients found that the C max was significantly increased and the T max was reduced when cyclosporine was given concomitantly with sirolimus compared with cyclosporine dosing 4 h after the sirolimus dose (Kaplan et al, 1998). This interaction was most likely due to altered bioavailability because a change in T max was observed and the increase in C max was much greater than the change in the sirolimus trough levels.…”

Section: Discussionmentioning

confidence: 86%

CYP3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and Midazolam

Cummins¹,

Jacobsen²,

Christians³

et al. 2003

J Pharmacol Exp Ther

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CYP3A4-transfected Caco-2 cells were used as an in vitro system to predict the importance of drug metabolism and transport on overall drug absorption. We examined the transport and metabolism of two drugs; midazolam, an anesthetic agent and CYP3A4 substrate, and sirolimus, an immunosuppressant and a dual CYP3A4/P-glycoprotein (P-gp) substrate, in the presence of cyclosporine (CsA, a CYP3A4/P-gp inhibitor) or N-{4- [2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine (GG918) (an inhibitor of P-gp and not CYP3A4). All major CYP3A4 metabolites were formed in the cells (1-OH Ͼ 4-OH midazolam and 39-O-desmethyl Ͼ 12-OH Ͼ 11-OH sirolimus), consistent with results from human liver microsomes. There was no bidirectional transport of midazolam across CYP3A4-transfected Caco-2 cells, whereas there was a 2.5-fold net efflux of sirolimus (1 M) that disappeared in the presence of CsA or GG918. No change in the absorption rate or extraction ratio (ER) for midazolam was observed when P-gp was inhibited with GG918. Addition of GG918 had a modest impact on the absorption rate and ER for sirolimus (increased 58% and decreased 25%, respectively), whereas a 6.1-fold increase in the absorption rate and a 75% decrease in the ER were found when sirolimus was combined with CsA. Although both midazolam and sirolimus metabolites were preferentially excreted to the apical compartment, only sirolimus metabolites were transported by P-gp as determined from inhibition studies with GG918. Using CYP3A4-transfected Caco-2 cells we determined that, in contrast to P-gp, CYP3A4 is the major factor limiting sirolimus absorption. The integration of CYP3A4 and P-gp into a combined in vitro system was critical to unveil the relative importance of each biochemical barrier.Oral bioavailability and intestinal drug absorption can be significantly limited by metabolizing enzymes and efflux transporters in the gut (Benet et al., 1996b). The most prevalent oxidative drug-metabolizing enzyme present in the intestine is cytochrome P450 3A4 (CYP3A4). Currently, more than 50% of the drugs on the market metabolized by P450 enzymes are metabolized by CYP3A4 (Benet et al., 1996a). Oral absorption of CYP3A4 substrates can also be limited by the multidrug resistance transporter P-glycoprotein (P-gp), because there is extensive substrate overlap between these two proteins (Wacher et al., 1995). P-gp is an ATP-dependent transporter on the apical plasma membrane of enterocytes that functions to limit the entry of drugs into the cell (Ambudkar et al., 1999). We have previously hypothesized that the interplay between CYP3A4 and P-gp in the intestine can serve to enhance drug metabolism and significantly decrease intestinal drug absorption (Cummins et al., 2002).

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Section: Discussionmentioning

confidence: 86%

CYP3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and Midazolam

Cummins¹,

Jacobsen²,

Christians³

et al. 2003

J Pharmacol Exp Ther

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“…A pharmacokinetic interaction has already been reported between calcineurin inhibitors and sirolimus (Kaplan et al, 1998;Cattaneo et al, 2004). Its mechanism mainly involves inhibition of the CYP 3A isoenzymes and, to a minor extent, inhibition of P-glycoprotein (Wacher et al, 2002;Cummins et al, 2004).…”

Section: Metabolism Of Sirolimus By Cyp 3a4 and Cyp 3a5mentioning

confidence: 99%

“…This can lead to pharmacokinetic interactions, as initially described in rats (Stepkowski et al, 1996). In renal transplant patients, coadministration of the two drugs resulted in increased sirolimus area under the concentration curve (1.45-fold), through concentration (1.49-fold) and maximal concentration (1.72-fold), compared with staggered administration, with no significant consequence on cyclosporine exposure (Kaplan et al, 1998). This interaction mainly involves CYP 3A inhibition as demonstrated in rats (Wacher et al, 2002) as well as in vitro using CYP 3A4-transfected Caco-2 cells (Cummins et al, 2004).…”

mentioning

confidence: 90%

Metabolism of Sirolimus in the Presence or Absence of Cyclosporine by Genotyped Human Liver Microsomes and Recombinant Cytochromes P450 3A4 and 3A5

Picard¹,

Djebli²,

Sauvage³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Sirolimus is an immunosuppressive drug currently used alone or in combination with cyclosporine. Both drugs undergo extensive metabolism by the CYP 3A enzymes. This study aimed at comparing the activity of recombinant CYP (rCYP) 3A4 and 3A5 toward sirolimus, investigating the effect of cyclosporine on the metabolic rate of these two cytochromes P450 (P450s), as well as the impact of the CYP 3A5*3 polymorphism on that of human liver microsomes (HLMs). Two distinct approaches were used; i.e., the measurement of (1) hydroxy-sirolimus and desmethyl-sirolimus production, and (2) sirolimus depletion by the in vitro half-life method. rCYP 3A5 exhibited a lower intrinsic clearance (CL int ) for both hydroxylation (0.11 versus 0.24 l/pmol P450/min) and depletion of sirolimus (0.64 versus 2.36 l/pmol P450/min) than rCYP 3A4. Similar CL int values for hydroxylation, demethylation, and depletion were found when comparing a pool of HLMs carrying at least one CYP 3A5*1 (active) allele with a pool of HLMs not expressing CYP 3A5. This was further confirmed for sirolimus depletion using individual microsome preparations (p ‫؍‬ 0.42). A deeper inhibitory effect of cyclosporine on the CL int of sirolimus depletion was found for rCYP 3A4 than for rCYP 3A5 (i.e., ؊44% versus ؊8% at 0.62 M, 750 g/l cyclosporine), and sirolimus metabolism was slightly less inhibited for HLMs expressing CYP 3A5 than not (؊38% versus ؊56%). In the absence of cyclosporine, the CYP 3A5*3 polymorphism may not influence significantly sirolimus metabolism at the hepatic level. However, strong CYP 3A4 inhibition by cyclosporine could unveil the influence of this polymorphism.

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“…The wide interpatient variability of sirolimus is largely attributed to the effects of intestinal cytochrome p450 3A enzymes (CYP3A) and P-glycoprotein activity on sirolimus absorption [16]. The coadministration of sirolimus and cyclosporine in renal transplant patients alters the bioavailability of sirolimus, increasing both the C max and area under the concentration-time curve (AUC) of sirolimus [28]. Sirolimus absorption was also shown to be reduced by the intake of a high-fat meal, although a 35% increase in AUC was reported [29].…”

Section: Pharmacokinetic Propertiesmentioning

confidence: 99%

mTOR Inhibitors in Tuberous Sclerosis Complex

Curatolo¹,

Moavero²

2012

Current Neuropharmacology

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Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.

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The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent*

Abstract: This study shows that the relative timing of administration of cyclosporine and sirolimus significantly affects the blood concentrations of sirolimus.

Cited by 114 publications

References 15 publications

CYP3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and Midazolam

CYP3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and Midazolam

Metabolism of Sirolimus in the Presence or Absence of Cyclosporine by Genotyped Human Liver Microsomes and Recombinant Cytochromes P450 3A4 and 3A5

mTOR Inhibitors in Tuberous Sclerosis Complex

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