Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog and human liver microsomes

Shiraga, Toshipumi; Matsuda, Hiroji; Nagase, Kazuko; Iwasaki, Katsunori; Noda, Kosei; Yamazaki, Hiroshi; Shimada, Tsutomu; Funae, Yoshihiko

doi:10.1016/0006-2952(94)90136-8

Cited by 119 publications

(63 citation statements)

References 24 publications

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“…Several drugs which are known CYP3A substrates such as diltiazem (K,: 70 p~) , lignocaine (K,,,: 119 p~) , prednisolone, and progesterone (K,,,: 65 p~) [IS] failed to inhibit significantly the in uitro metabolism of [9] at the concentrations tested. The more than 10-fold higher K , values of these drugs compared with that of tacrolimus may provide a basis for their lack of inhibitory effect.…”

Section: Resultsmentioning

confidence: 99%

Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes

Christians

Schmidt

Bader

et al. 1996

Brit J Clinical Pharma

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1 Tacrolimus, an immunosuppressive macrolide, is metabolized by enzymes of the cytochrome P450 3A subfamily. In this study, 34 drugs were tested for their interactions with tacrolimus metabolism by human liver microsomes. 2 Fifteen drugs which inhibit the in vitro metabolism of tacrolimus were identified: bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinyloestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin and verapamil.Keywords tacrolimus metabolism drug interactions 13-0-demethyl tacrolimus human microsomes cytochrome P450 3A

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Section: Resultsmentioning

confidence: 99%

Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes

Christians

Schmidt

Bader

et al. 1996

Brit J Clinical Pharma

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“…Recently, genes encoding methoxymalonyl-ACP biosynthesis from the ansamitocin gene cluster of Actinosynnema pretiosum were co-expressed along with the engineered DEBS genes in S. lividans, and the resulting strain produced 2-methoxy-2-demethyl-6-DEB. 5 This shows that ascomycin AT8 maintains its original substrate preference in this foreign context. On the other hand, our results also suggest that changing the context of an AT domain can affect substrate selectivity.…”

Section: Fig 3 Structure Of 6-deb and Potential Analogues S Lividansmentioning

confidence: 87%

“…polyketide chain. Finally, if hydroxymalonyl units were incorporated at these positions, the polyketide would rearrange to form the hemiketal isomers known to be favored following demethylation of these methoxy groups by mammalian liver CYP3A (4,5), and this could interfere with subsequent biosynthetic steps. Our previous proposal that the substrate is methoxymalonyl-ACP instead of methoxymalonyl-CoA was based on the presence of an unusual ACP gene (fkbJ) in the set of five genes believed to encode the synthesis of this extender unit (14).…”

Section: Fig 3 Structure Of 6-deb and Potential Analogues S Lividansmentioning

confidence: 99%

“…Dosing of tacrolimus is difficult because metabolism varies between patients and different co-administered drugs (1)(2)(3). Because initial metabolism is due to cytochrome P450-mediated demethylation of the 13-methoxy group (4,5), we wished to replace the 13-methoxy group with a hydrogen or methyl group and determine whether this increased metabolic stability. Because these analogues could not be obtained by current chemical methods, we sought the desired analogues of ascomycin modified at C13 (Fig.…”

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confidence: 99%

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A New Substrate Specificity for Acyl Transferase Domains of the Ascomycin Polyketide Synthase in Streptomyces hygroscopicus

Reeves¹,

Chung²,

Liu³

et al. 2002

Journal of Biological Chemistry

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Ascomycin (FK520) is a structurally complex macrolide with immunosuppressant activity produced by Streptomyces hygroscopicus. The biosynthetic origin of C12-C15 and the two methoxy groups at C13 and C15 has been unclear. It was previously shown that acetate is not incorporated into C12-C15 of the macrolactone ring. Here, the acyl transferase (AT) of domain 8 in the ascomycin polyketide synthase was replaced with heterologous ATs by double homologous recombination. When AT8 was replaced with methylmalonyl-CoA-specific AT domains, the strains produced 13-methyl-13-desmethoxyascomycin, whereas when AT8 was replaced with a malonyl-specific domain, the strains produced 13-desmethoxyascomycin. These data show that ascomycin AT8 does not use malonyl-or methylmalonyl-CoA as a substrate in its native context. Therefore, AT8 must be specific for a substrate bearing oxygen on the ␣ carbon. Feeding experiments showed that [ 13 C]glycerol is incorporated into C12-C15 of ascomycin, indicating that both modules 7 and 8 of the polyketide synthase use an extender unit that can be derived from glycerol. When AT6 of the 6-deoxyerythronolide B synthase gene was replaced with ascomycin AT8 and the engineered gene was expressed in Streptomyces lividans, the strain produced 6-deoxyerythronolide B and 2-demethyl-6-deoxyerythronolide B. Therefore, although neither malonylCoA nor methylmalonyl-CoA is a substrate for ascomycin AT8 in its native context, both are substrates in the foreign context of the 6-deoxyerythronolide B synthase. Thus, we have demonstrated a new specificity for an AT domain in the ascomycin polyketide synthase and present evidence that specificity can be affected by context. Ascomycin (FK520) is closely related to tacrolimus (FK506), which is used to prevent xenograft rejection in human patients. Dosing of tacrolimus is difficult because metabolism varies between patients and different co-administered drugs (1-3). Because initial metabolism is due to cytochrome P450-mediated demethylation of the 13-methoxy group (4, 5), we wished to replace the 13-methoxy group with a hydrogen or methyl group and determine whether this increased metabolic stability. Because these analogues could not be obtained by current chemical methods, we sought the desired analogues of ascomycin modified at C13 (Fig. 1) using PKS 1 engineering (6, 7). The macrolactone precursor of ascomycin is biosynthesized by a large PKS complex consisting of a loading module for a shikimate-derived starter unit; 10 modules for malonyl, methylmalonyl, or other PKS extender units; and a peptide synthetase module for addition of pipecolate (8 -13). FK520 and FK506 have methoxy groups at C13 and C15, which could be derived by post-PKS hydroxylation followed by O-methylation or by direct incorporation of an extender unit with an oxygen at the ␣ carbon. Feeding of [ 13 C 2 ]acetate was reported to label C8-C9 and C20-C23 of the macrolactone ring, as expected, but not C12-C15 in either FK520 or FK506 (8). A [1-13 C]erythrose feed, used to establish that the dihydrox...

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“…27,[38][39][40][41] Less than 1% of an intravenous or oral dose is found in the urine. 27,42 The drug undergoes demethylation, hydroxylation and conjugation in the liver with most of the metabolites, and possibly conjugates, of tacrolimus eliminated in the bile.…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

Jacobson

Uberti

Davis

et al. 1998

Bone Marrow Transplant

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Summary:Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

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Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog and human liver microsomes

Cited by 119 publications

References 24 publications

Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes

Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes

A New Substrate Specificity for Acyl Transferase Domains of the Ascomycin Polyketide Synthase in Streptomyces hygroscopicus

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

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