Untitled

Kim, R. B.; Wandel, C.; Leake, Brenda F.; Cvetković, Mirjana; Fromm, Martin F.; Dempsey, Peter J.; Roden, M. M.; Belas, Frank J.; Chaudhary, Archana; Roden, Dan M.; Wood, Alastair J.J.; Wilkinson, Grant R.

doi:10.1023/a:1018877803319

Cited by 406 publications

(28 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies find that many substrates of MDR1 are also substrates of drug-metabolizing enzymes, such as CYP3A4. This overlap may be to some extent a result of a coordinated regulation of tissue expression of CYP3A4 and MDR1 (both of which are located in close proximity on the same chromosome) in organs such as the liver and intestine [56]. However, such overlap is not always present; some MDR1 substrates, such as digoxin, fexofonadine, celiprolol, and tarlinolol do not significantly interact with CYP enzymes and others, such as midazolam, are not transported by MDR1 [56]- [58].…”

Section: Abc-transporter Substratesmentioning

confidence: 99%

“…Therefore, it is essential to understand how CYP3A4 interacts with MDR1 inhibitors when using them in combination with cytotoxic drugs. In addition, reversal agents, which have MDR1 inhibition effects, also inhibit cytochrome P-450 3A (CYP3A) activity [56]. Herbs or drugs may inhibit CYPs by three mechanisms: competitive inhibition, noncompetitive inhibition, and mechanism-based inhibition [76].…”

Section: Cytochrome P450mentioning

confidence: 99%

See 1 more Smart Citation

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

Eid¹,

El-Readi²,

Fatani³

et al. 2015

View full text Add to dashboard Cite

show abstract

Section: Abc-transporter Substratesmentioning

confidence: 99%

Section: Cytochrome P450mentioning

confidence: 99%

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

Eid¹,

El-Readi²,

Fatani³

et al. 2015

View full text Add to dashboard Cite

show abstract

“…This serendipitous observation was confirmed in two additional patients, who were treated with mitotane and also showed markedly induced midazolam metabolism. Since midazolam is mainly metabolized by CYP3A4 with little affinity for CYP3A5, ABCB1, and ABCG2, our observation is most likely the result of a strong inducing effect of mitotane on CYP3A4 activity (14,24,25). The small number of patients in this report may seem as a limitation.…”

Section: Discussionmentioning

confidence: 76%

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Erp

Guchelaar

Ploeger³

et al. 2011

European Journal of Endocrinology

103

View full text Add to dashboard Cite

Objective: The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib. Design: A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods: Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment. Results: The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC 0-12 h (95% CI): 7.6 (5.5-9.7) vs 139.0 (95.1-182.9) mg!h/l respectively PZ0.001) and increased 1-hydroxy-midazolam exposure (mean AUC 0-12 h (95% CI): 409.6 (290.5-528.7) vs 35.0 (26.4-43.6) mg!h/l, PZ0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 mg!h/l versus 1344 (1079-1609) (mean (95% CI)) mg!h/l). Conclusion: Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzyme.

show abstract

“…23) Many of the CYP3A substrates also act as substrates for P-glycoprotein (P-gp), a transporter that mediates drug excretion. 30,31) However, triazolam is not a P-gp substrate. 32) Therefore, triazolam was intraperitoneally administered to mice that were fed either the control diet or MF diet for 4 weeks, and the plasma concentration of triazolam was measured to calculate its pharmacokinetic parameters (Fig.…”

Section: Fig 5 Triazolam Pharmacokineticsmentioning

confidence: 99%

Different Diets Cause Alterations in the Enteric Environment and Trigger Changes in the Expression of Hepatic Cytochrome P450 3A, a Drug-Metabolizing Enzyme

Tajima

Ikarashi

Igeta

et al. 2013

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Changes in the expression level and activity of cytochrome P450 (CYP) in the liver are caused by various factors and affect the pharmacokinetics of drugs. The purpose of this study was to determine whether the expression of CYP3A is affected by a high-fat diet. In addition, we examined whether the type of diet given to mice could produce changes in the expression level and activity of CYP3A. Mice were fed a purified diet containing 10 kcal% lard (control group) or 60 kcal% lard (HF group) or regular mouse chow containing 13 kcal% of fat (MF group) for 4 weeks. No significant differences were observed in the hepatic CYP3A protein expression level between the HF group and the control group. The CYP3A protein expression in the MF group was significantly higher than that observed in the control group. In the MF group, the area under the curve (AUC) of intraperitoneally administered triazolam was lower. Because lithocholic acid (LCA) is known to increase hepatic CYP3A expression, the levels of Clostridium sordellii and LCA in the feces were measured. In the MF group, the levels of Clostridium sordellii and LCA were higher. It has been demonstrated that a high-fat diet does not cause any changes in hepatic CYP3A expression. In addition, the different diets caused alterations in the enteric environment, which triggered changes in CYP3A expression. Therefore, it is necessary to carefully consider the type of feed while performing animal experiments to evaluate the pharmacokinetics of drugs.

show abstract

Untitled

Abstract: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.

Cited by 406 publications

References 22 publications

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Different Diets Cause Alterations in the Enteric Environment and Trigger Changes in the Expression of Hepatic Cytochrome P450 3A, a Drug-Metabolizing Enzyme

Contact Info

Product

Resources

About