Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene

Lehtinen, Terhi; Tolonen, Ari; Turpeinen, Miia; Uusitalo, Jouko; Vuorinen, Jouni; Lammintausta, Risto; Pelkonen, Olavi; Scheinin, Mika

doi:10.1002/bdd.1853

Cited by 10 publications

(6 citation statements)

References 18 publications

(21 reference statements)

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“…The previous reported HPLC method (Taras et al, ) was developed with 1 mL plasma and used toremifene citrate as the internal standard with a run time of >12.0 min. The reported UPLC–MS method (Lehtinen et al, ), was used to determine CYP enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examined the effects of CYP inhibitors and inducers rifampicin, ketoconazole, fluconazole and omeprazole on the pharmacokinetics of ospemifene. In the present method a highly sensitive and rapid method was developed and validated from 5.02 to 3025 ng/mL using 200 μK plasma with stable labeled isotope ospemifene d4 as internal standard in a shorter run time of 3.0 min.…”

Section: Discussionmentioning

confidence: 99%

“…The conventional HPLC method takes more time for resolution and requires a greater plasma volume. Lehtinen et al () reported an UPLC–MS method to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics. This method was developed for metabolite identification and examined the effects of pretreatment with CYP modulators.…”

Section: Introductionmentioning

confidence: 99%

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Determination of ospemifene in human plasma by LC–MS/MS and its application to a human pharmacokinetic study

Yadlapalli

Katari

Surya

2019

Biomedical Chromatography

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A highly sensitive, specific and rapid liquid chromatography–tandem mass spectrometry (LC–MS/MS) analytical method has been developed and validated for the determination of ospemifene in human plasma using ospemifene‐d4 as an internal standard. Solid‐phase extraction technique with Phenomenex Strata X‐33 μm polymeric sorbent cartridges (30 mg/1 mL) was used to extract the analytes from the plasma. The chromatographic separation was achieved on Agilent Eclipse XDB‐Phenyl, 4.6 × 75 mm, 3.5 μm column using the mobile phase composition of methanol and 20 mm ammonium formate buffer (90:10, v/v) at a flow rate of 0.9 mL/min. A detailed method validation was performed as per the US Food and Drug Administration guidelines and the calibration curve obtained was linear (r2 = 99) over the concentration range 5.02–3025 ng/mL. The API‐4500 MS/MS was operated under multiple reaction monitoring mode during the analysis. The proposed method was successfully applied to a pharmacokinetic study in healthy human volunteers after oral administration of an ospemifene 60 mg tablet under fed conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determination of ospemifene in human plasma by LC–MS/MS and its application to a human pharmacokinetic study

Yadlapalli

Katari

Surya

2019

Biomedical Chromatography

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“…This drug was an original discovery of Hormos Medical, a Finnish drug development company based in Turku, Finland. Together with Novamass, we contributed to the elucidation of in vitro and in vivo metabolic and pharmacokinetic characteristics of ospemifene, and the results were published recently . Ospemifene has been the most visible milestone of our contributions to drug development.…”

Section: Development Of In Vitro and In Silico Methods For Drug Develmentioning

confidence: 99%

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Pelkonen

2015

Basic Clin Pharma Tox

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Drug metabolism is the crucial part of pharmaco-and toxicokinetics and consequently is associated with both desirable and adverse effects of most xenobiotics, compounds foreign to the body. This minireview follows some advances of the field over the last 50 years or so through the experiences and work of one scientist. Thus, this minireview represents a rather personal view of research in one research field. Drug metabolism is affected and controlled by a huge number of factors and conditions such as individual development, species differences, drug-drug interactions and various environmental, host and genetic factors working via a variable set of regulatory mechanisms. All these different factors create wide individual, population and species variability with obvious repercussions to clinical drug therapy and chemical risk assessment. This minireview also provides glimpses to methodological developments over recent decades and ends up presenting a few promising approaches and techniques such as various omics and high-content and high-throughput techniques feeding huge amounts of data to computational integration and modelling, which constitute the basis for systems or network pharmacology and toxicology.

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“…Therefore, rifampin, ketoconazole and fluconazole should not be prescribed to women taking ospemifene. 36 Coadministration of ospemifene with drugs that inhibit CYP450 3A4 (CYP3A4) and CYP450 2C9 (CYP2C9) may also increase the risk of adverse reactions.…”

Section: Drug Interactionsmentioning

confidence: 99%

Ospemifene: A Novel Option for the Treatment of Vulvovaginal Atrophy

et al. 2017

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Ospemifene—a third-generation selective estrogen receptor modulator approved by the Food and Drug Administration in 2013—is an oral medication for the treatment of dyspareunia. In postmenopausal women with vulvovaginal atrophy, ospemifene significantly improves the structure and pH levels of the vagina, reducing dyspareunia. It is available as a 60-mg tablet; hence, women who may have had prior difficulty with vaginal administration or on-demand use of nonprescription lubricants and moisturizers would likely prefer this form of treatment. Preclinical studies demonstrated that ospemifene has an estrogen agonist action on the bone, reducing the cell proliferation of ductal carcinoma in an in situ model. Studies evaluating the safety of treatment for up to 52 weeks have shown that ospemifene is a safe medication with minimal impact on the endometrium. Further studies with larger number of subjects are necessary to better conclude its effects and long-term safety.

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Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene

Cited by 10 publications

References 18 publications

Determination of ospemifene in human plasma by LC–MS/MS and its application to a human pharmacokinetic study

Determination of ospemifene in human plasma by LC–MS/MS and its application to a human pharmacokinetic study

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Ospemifene: A Novel Option for the Treatment of Vulvovaginal Atrophy

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