Terbinafine‐associated inhibition of dextromethorphan metabolism in Chinese subjects

Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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“…The intensity of inhibition may also be sensitive to ethnicity, which is probably also a genetic effect [54][55][56].…”

Section: Duration Of Phenoconversionmentioning

confidence: 99%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

219

217

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“…For example, a clinical study involving concomitant use of TER and the antidepressant desipramine found increased plasma desipramine concentrations when desipramine was given at a 4-week interval after oral administration of TER for 21 consecutive days, 3) and another clinical study involving concomitant use of TER and the antitussive dextromethorphan showed that a period of more than 3 months was required for the dextromethorphan/dextrorphan metabolism ratio to return to the level observed in the absence of concomitant TER after oral administration of TER for 14 consecutive days. 5) These findings may be viewed as representing interactions arising from the long persistence of the CYP2D6-inhibitory effect of TER. It is important to note that CYP2D6 substrate drugs include many in wide clinical use, including circulatory drugs and beta blockers.…”

Section: Discussionmentioning

confidence: 99%

“…TER also increased the plasma concentration of paroxetine 4) and the urinary dextromethorphan/dextrophan ratio. 5,6) TER interactions are characterized by long persistence; for example, concomitant use of the antipsychotic perphenazine and TER led to appearance of an extrapyramidal symptom (marked akathisia), which persisted for 3 weeks following discontinuation of TER. 7) With regard to amitriptyline (AT) and nortriptyline (NT), it has been reported that concomitant administration with TER greatly increased the plasma concentration of AT or NT, inducing adverse drug reactions such as thirst, nausea, and vertigo that persisted for a long time following discontinuation of TER.…”

mentioning

confidence: 99%

Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline

Mikami

Hori

Ohtani

et al. 2017

Biological & Pharmaceutical Bulletin

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The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound K values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound K values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

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Current Awareness

2001

Pharmacoepidemiology and Drug

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of pharmacoepidemiology and drug safety. Each bibliography is divided into 19 sections: 1 Books, Reviews & Symposia; 2 General; 3 Anti‐infective Agents; 4 Cardiovascular System Agents; 5 CNS Depressive Agents; 6 Non‐steroidal Anti‐inflammatory Agents; 7 CNS Agents; 8 Anti‐neoplastic Agents; 9 Haematological Agents; 10 Neuroregulator‐Blocking Agents; 11 Dermatological Agents; 12 Immunosuppressive Agents; 13 Autonomic Agents; 14 Respiratory System Agents; 15 Neuromuscular Agents; 16 Reproductive System Agents; 17 Gastrointestinal System Agents; 18 Anti‐inflammatory Agents ‐ Steroidal; 19 Others. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

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Terbinafine‐associated inhibition of dextromethorphan metabolism in Chinese subjects

Cited by 5 publications

References 5 publications

Addressing phenoconversion: the Achilles' heel of personalized medicine

Addressing phenoconversion: the Achilles' heel of personalized medicine

Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline

Current Awareness

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