2002
DOI: 10.1046/j.1472-8206.2002.00114.x
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In vitro effects of tacrolimus on human cytochrome P450

Abstract: Tacrolimus, a potent immunosuppressive drug, is known to be metabolized predominantly in the liver by cytochrome P450 3A (CYP3A). In order to determine the potential of tacrolimus to inhibit the metabolism of other drugs, we have investigated its inhibitory effects on specific cytochrome reactions. Specific substrates for the seven cytochromes (CYPs) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4/5 were incubated with human hepatic microsome preparations with or without specific inhibitors or tacrolimus and the metabol… Show more

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Cited by 20 publications
(20 citation statements)
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“…This result is in accordance with previous in vitro studies, mainly in HLMs, showing competitive inhibition and K i values in the range of 0.36 to 3.7 M (Wandel et al, 1999;Lecointre et al, 2002;Niwa et al, 2007). However, it is worth mentioning that Lecointre et al (2002), who reported a 6-fold higher K i value than that in the present study (3.7 M), applied a substrate concentration of MDZ (15 M) approximately 10 times higher than the K m value, i.e., not optimal conditions for inhibition experiments. In insect microsomes Tac was showing time-dependent and NADPH-dependent inhibition, which may suggest a mechanism-based inhibitory effect.…”
Section: Downloaded Fromsupporting
confidence: 82%
See 1 more Smart Citation
“…This result is in accordance with previous in vitro studies, mainly in HLMs, showing competitive inhibition and K i values in the range of 0.36 to 3.7 M (Wandel et al, 1999;Lecointre et al, 2002;Niwa et al, 2007). However, it is worth mentioning that Lecointre et al (2002), who reported a 6-fold higher K i value than that in the present study (3.7 M), applied a substrate concentration of MDZ (15 M) approximately 10 times higher than the K m value, i.e., not optimal conditions for inhibition experiments. In insect microsomes Tac was showing time-dependent and NADPH-dependent inhibition, which may suggest a mechanism-based inhibitory effect.…”
Section: Downloaded Fromsupporting
confidence: 82%
“…The majority of these studies have been performed using pooled human liver microsomes (HLMs), but rat liver microsomes and recombinant systems have also been used, in combination with more or less specific probe substrates (Jacobsen et al, 1999;Wandel et al, 1999;Paine et al, 2000;Lecointre et al, 2002;Niwa et al, 2007;Picard et al, 2007). Most of these studies indicate that the inhibitory capacity of both CsA and Tac is too low to be clinically relevant.…”
Section: Introductionmentioning
confidence: 99%
“…Therefore, the actual recovery of CYP3A activity after kidney transplantation may be earlier than the results in this study. Second, it has been reported that basiliximab may inhibit CYP3A, although tacrolimus, mycophenolic acid, and methylprednisolone have no potency to inhibit or induce CYP3A (36)(37)(38)(39)(40). Then, recovery of CYP3A activity may be slightly masked after induction therapy with basiliximab.…”
Section: Discussionmentioning
confidence: 99%
“…These results in the eŠects of tacrolimus on support the results of the previous study which found that tacrolimus has no eŠect on CYP1A2, CYP2C9,CYP2D6, CYP2E1, and CYP3A4 at concentrations below 1 mM, but it has a slightly competitive inhibitory eŠect on CYP3A4 activity, with K i values of 2-3.7 mM, which suggests that tacrolimus is unlikely to potentiate the eŠect of co-administered drugs through inhibition of hepatic metabolism. 31) In addition, the K i values of cyclosporine and tacrolimus against CYP3A4-mediated estradiol 2-hydroxylation are reported to be 0.30 and 0.88 mM, respectively. 27) Since substrate-dependent eŠects on CYP3A4-inhibition potential have been reported previously, 26,29) this study focused on the estimation of the degree of the CYP3A4-inhibition by the use of other typical CYP3A4-substrates, nifedipine and testosterone.…”
Section: Discussionmentioning
confidence: 99%