Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors

Kumondai, Masaki; Kikuchi, Masafumi; Mizuguchi, Atsushi; Hayashi, Nagomi; Ui, Masahiro; Hirama, Takashi; Okada, Yoshinori; Sato, Yu; Sato, Toshihiro; Maekawa, Masamitsu; Mano, Nariyasu

doi:10.1620/tjem.2023.j016

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…Moreover, clarithromycin forms a MIC with CYP3A, which may result in a pharmacokinetic interaction that interferes with the clearance of sirolimus through CYP3A [ 9 ]. Patients who received clarithromycin during sirolimus treatment have been reported to exhibit increased blood levels of sirolimus [ 4 ]. Although there are no direct reports linking the concentration of sirolimus in the blood to the onset of acneiform eruptions, the occurrence of acneiform eruptions has been reported to be higher in groups receiving a high dose of sirolimus [ 5 ], suggesting that the increased blood levels of sirolimus due to clarithromycin administration might have led to the development of the acneiform eruption in this case.…”

Section: Discussionmentioning

confidence: 99%

“…Clarithromycin is a macrolide antibiotic that inhibits RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunit of susceptible bacteria [ 3 ]. Clarithromycin inhibits cytochrome P450 3A (CYP3A)-mediated drug clearance by forming a metabolic intermediate complex (MIC) with CYP3A, thus contributing to increased blood levels of sirolimus [ 4 ]. Here, we report a case of acneiform eruptions potentially triggered by clarithromycin during sirolimus treatment.…”

Section: Introductionmentioning

confidence: 99%

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Acneiform Eruptions Possibly Triggered by Clarithromycin During Sirolimus Treatment

Kataoka,

Nakajima,

Nomura

et al. 2024

Cureus

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Acneiform eruption is the recognized dermatological side effect of sirolimus, an inhibitor of the mammalian target of rapamycin, although the pathophysiological mechanisms and dose dependency of this side effect remain unclear. This case report describes a case of a 40-year-old Japanese woman treated with systemic sirolimus who developed acneiform eruptions following the administration of clarithromycin. The acneiform eruption resolved after discontinuation of sirolimus and relapsed with the resumption. Since sirolimus and clarithromycin have a potential drug-drug interaction mediated by cytochrome P450 3A (CYP3A), this case suggests that the acneiform eruption developed in association with elevated blood levels of sirolimus. We conclude that clinicians should be aware of the possibility of developing acneiform eruption during sirolimus treatment, especially when administered with medications that inhibit CYP3A.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acneiform Eruptions Possibly Triggered by Clarithromycin During Sirolimus Treatment

Kataoka,

Nakajima,

Nomura

et al. 2024

Cureus

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“…Drug interactions via transporters and metabolic enzymes are considered the main cause of adverse drug reactions [15,16]; thus, drug-drug and drug-endogenous metabolite interaction studies have been widely conducted [17][18][19][20][21]. Quercetin, a flavonoid, has been reported to increase the plasma concentration of pravastatin by inhibiting organic aniontransporting polypeptide (OATP) 1B1 [22].…”

Section: Introductionmentioning

confidence: 99%

The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation

Sato,

Yagi,

Yamauchi

et al. 2024

IJMS

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Flavonoids have garnered attention because of their beneficial bioactivities. However, some flavonoids reportedly interact with drugs via transporters and may induce adverse drug reactions. This study investigated the effects of food ingredients on organic anion-transporting polypeptide (OATP) 4C1, which handles uremic toxins and some drugs, to understand the safety profile of food ingredients in renal drug excretion. Twenty-eight food ingredients, including flavonoids, were screened. We used ascorbic acid (AA) to prevent curcumin oxidative degradation in our method. Twelve compounds, including apigenin, daidzein, fisetin, genistein, isorhamnetin, kaempferol, luteolin, morin, quercetin, curcumin, resveratrol, and ellagic acid, altered OATP4C1-mediated transport. Kaempferol and curcumin strongly inhibited OATP4C1, and the Ki values of kaempferol (AA(−)), curcumin (AA(−)), and curcumin (AA(+)) were 25.1, 52.2, and 23.5 µM, respectively. The kinetic analysis revealed that these compounds affected OATP4C1 transport in a competitive manner. Antioxidant supplementation was determined to benefit transporter interaction studies investigating the effects of curcumin because the concentration-dependent curve evidently shifted in the presence of AA. In this study, we elucidated the food–drug interaction via OATP4C1 and indicated the utility of antioxidant usage. Our findings will provide essential information regarding food–drug interactions for both clinical practice and the commercial development of supplements.

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Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice

Kumondai,

Ogawa,

Hayashi

et al. 2024

Pharmacology Res & Perspec

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Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β‐hydroxycortisol, deoxycholic acid, and 1β‐hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography–tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three‐compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

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Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors

Abstract: Therapeutic drug monitoring of blood sirolimus and tacrolimus concentrations for polypharmacy management in a lymphangioleiomyomatosis patient taking two cytochrome P450 3A inhibitors

Cited by 5 publications

References 26 publications

Acneiform Eruptions Possibly Triggered by Clarithromycin During Sirolimus Treatment

Acneiform Eruptions Possibly Triggered by Clarithromycin During Sirolimus Treatment

The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation

Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice

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