Metabolism Of Dextromethorphan Research Articles

Maintenance of antidepressant effect by dextromethorphan in patients with treatment-resistant depression who respond to ketamine intervention

Although conventional oral antidepressants are effective in patients with major depressive disorder (MDD), up to 30% of these patients do not achieve symptomatic remission, even after undergoing two trials of antidepressants. Such patients are classified as having treatment-resistant depression (TRD). The glutamate neurotransmitter system has attracted attention as a potential target for treatment that may serve as an alternative to antidepressant treatment. Ketamine is a prototypical N-methyl-d-aspartate receptor (NMDAR) antagonist that has demonstrated substantial promise as a rapid-acting antidepressant for patients with TRD. A single infusion of ketamine causes a noticeable antidepressant effect within 4 h, which peaks after 24 h and then gradually declines. Sustaining the initial clinical response to ketamine infusion in patients with TRD is a major clinical challenge. Dextromethorphan and ketamine share similar pharmacological properties, including their effects on NMDARs, mu-opioid receptors, and sigma-1 receptors. The pathogenesis of MDD, a complex and heterogeneous disorder, has been linked to multiple neurotransmitter systems. Patients with TRD who favorably respond to acute ketamine treatment are likely to respond well to subsequent dextromethorphan therapy. Therefore, we hypothesized that dextromethorphan could sustain the antidepressant effect of ketamine infusion. Because of the rapid and extensive metabolism of dextromethorphan by cytochrome P450 2D6 (CYP2D6), a high dose of dextromethorphan or a combination of dextromethorphan with CYP2D6 inhibitors is required to maintain the antidepressant effect of ketamine.

Abstract CT273: Evaluation of the effect of rivoceranib on the pharmacokinetics of cytochrome P450 enzyme substrates in healthy volunteers

Abstract Introduction: Rivoceranib is a selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with potent antitumor activity. Rivoceranib is metabolized in the liver mostly by cytochrome P450 (CYP)3A4/5, with minor contributions from CYP2D6, CYP2C9, and CYP2E1. In vitro and in vivo studies suggest rivoceranib may interact with various CYP substrates, including CYP 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. The purpose of study is to evaluate the effect of rivoceranib on the pharmacokinetics (PK) of various CYP substrates. Methods: This study was an open-label, 2-treatment, fixed-sequence drug-drug interaction phase 1 study evaluating the impact of multiple oral doses of 700 mg rivoceranib on the single-dose PK of CYP enzyme substrates administered in a 5+1 probe cocktail (caffeine [CYP1A2], S- and R-warfarin [CYP2C9] + vitamin K, omeprazole [CYP2C19], dextromethorphan [CYP2D6], and midazolam [CYP3A]) in healthy volunteers (N=32). On day 1, volunteers received a single dose of the 5+1 cocktail comprising 200 mg caffeine, 10 mg S- and R-warfarin with 10 mg vitamin K, 40 mg omeprazole, 30 mg dextromethorphan, and 2 mg midazolam. Blood samples were collected predose on day 1 and up to 120 hours post-dose for PK analyses of the substrates in the 5+1 cocktail. On days 6 to 15, volunteers received 700 mg rivoceranib once daily for 10 consecutive days with a single dose of the 5+1 cocktail administered on day 11. Blood samples were collected predose on day 11 and up to 120 hours post cocktail dosing (day 16) for PK analyses. Each dosing was under fasted conditions. There was a washout period of 5 days between Day 1 dosing and the first rivoceranib dose on Day 6; the 2 cocktail dosings were spaced by 10 days. Results: Rivoceranib reduced caffeine AUC0-inf by 15%, and did not change caffeine Cmax, indicating a minimal effect of rivoceranib on the PK of CYP1A2 substrates. S-warfarin and R-warfarin AUC0-inf increased by 68% and 32%, respectively, and Cmax by 19% and 15%, respectively, when co-administered with rivoceranib, indicating rivoceranib weakly inhibits CYP2C9. Rivoceranib appeared to act as a moderate inhibitor of CYP2C19, increasing omeprazole AUC0-inf 3.3-fold and increasing Cmax 2-fold. Dextromethorphan metabolism (CYP2D6) was inhibited, with a 2- to 2.7-fold increase in dextromethorphan exposure. Rivoceranib appeared to moderately inhibit midazolam metabolism by CYP3A4, with 2.4- to 2.8-fold increases in midazolam exposures. Conclusion: In the analysis, the effect of rivoceranib on the PK of CYP1A2 substrates did not appear to be clinically significant. Rivoceranib may inhibit the metabolism of CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates, suggesting that dose adjustment of substrates of these CYP isozymes and/or cautiously monitoring patients’ adverse events may be needed when they are co-administered with rivoceranib. Citation Format: Janelle Weyer, Xianzhang Meng, Jennifer Lee, Joseph Reitano, Vinoo Urity, Cheol-Hee Park, Bill Strickland, Jan Van Tornout, Seong Jang. Evaluation of the effect of rivoceranib on the pharmacokinetics of cytochrome P450 enzyme substrates in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT273.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Impact of Interferons and Biological Drug Inhibitors of IL-2 and IL-6 on Small-Molecule Drug Metabolism Through the Cytochrome P450 System.

Assess the impact of interferons and interleukin (IL)-2 and IL-6 inhibitors on cytochrome P450 (CYP) drug metabolism in human subjects. PubMed search from 1980 to March 31, 2021, limited to human subjects and English language via search strategy: (biological drug names) [AND] (cytochrome [OR] CYP metabolism). Narrative review of human studies assessing biological drugs in select classes that affect CYP drug metabolism. Exogenous interferons suppress CYP1A2 (theophylline, caffeine, antipyrone) clearance by 20% to 49% in patients; have minimal impact on CYP3A4 (midazolam and dapsone), CYP2C9 (tolbutamide), or CYP2C19 (mephenytoin) metabolism; and increase CYP2D6 (debrisoquine, dextromethorphan) metabolism. Biological IL-2 inhibitors (basiliximab, daclizumab) have no effect on metabolism via CYP1A2 (caffeine), CYP2C9 (s-warfarin), CYP2C19 (omeprazole), CYP2D6 (dextromethorphan), and CYP3A4 (midazolam, tacrolimus) but may enhance CYP3A4 (cyclosporin) metabolism over time. IL-6 inhibitors (sirukumab, tocilizumab, sarilumab) significantly enhance metabolism via CYP2C9 (s-warfarin), CYP2C19 (omeprazole), and CYP3A4 (simvastatin, midazolam) and reduce metabolism via CYP1A2 (caffeine). Patients using interferons, IL-2, or IL-6 blocking drugs at steady state with CYP substrates could have altered drug metabolism and experience adverse events. With interferons and biological anti-inflammatory drugs, some isoenzymes will be inhibited, whereas others will be enhanced, and the magnitude of the effect can sometimes be significant. In clinical practice, clinicians may consider these metabolic changes as an additive effect to a patient's entire disease and medication profile when determining risk/benefit of treatment. Interferon therapy or inflammatory suppression via IL-2 or IL-6 can alter steady-state concentrations of CYP-metabolized small-molecule drugs.

Effect of Vernonia Amygdalina Leaf on Cytochrome P450 2D6- and 3A4-Mediated Metabolism of Dextromethorphan in Healthy Nigerian Subjects

Back-ground and Objectives: The study’s focus is to investigate the effects of Vernonia amygdalina on the metabolic activities of Cytochrome P450 3A4 and 2D6 in vivo. The assessment was based on CYP2D6-mediated O-demethylation and CYP3A4-mediated N-demethylation of dextromethorphan (DEX) to Dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively.
 Methods: The clinical study followed a two-phase cross over study with two weeks washout period. Volunteers received a single oral dose of DEX 30 mg alone in phase 1 and along with last dose of V. amygdalina leaf powder in phase 2. 8-hour urine samples were collected in both phases post-administration of DEX and analyzed using HPLC-UV. The chromatographic separation of DEX, DOR, 3-MM, and Imatinib was achieved on a C18 column. The analytes were eluted with a gradient elution consisting of 50mM potassium dihydrogen phosphate (pH 5)-acetonitrile at a 1 mL/min flow rate, and detected at 280 nm. Activities of the enzymes investigated were evaluated using the urinary metabolic ratios of DEX:DOR and DEX:3-MM.
 Results: Median (interquartile range) values for the metabolic ratios of DEX:DOR was 0.032 (0.028-0.246) and 0.029 (0.018-0.061) for phases with and without V. amygdalina respectively, while the average median values for DEX:3MM was 5.087 (3.692-71.420) and 5.609 (3.093-19.197) for phases with and without V. amygdalina respectively. However, the differences between both phases were not significant for both isoenzymes.
 Conclusion: V. amygdalina does not significantly affect the activities of CYP2D6 and CYP3A4 In vivo, which indicates that it has minimal potential to interact with the substrates of both isoenzymes.

Tryptophan-75 Is a Low-Energy Channel-Gating Residue that Facilitates Substrate Egress/Access in Cytochrome P450 2D6.

CYP2D6 is a major drug metabolizing enzyme with a buried active site. Channels leading to the active site from various enzyme surfaces are believed to facilitate ligand egress and access to the active site. The present study used molecular dynamics (MD) and in vitro studies with CYP2D6*1 and a Trp75-to-Ala mutant to examine channel gating in CYP2D6 by Trp75. MD simulations measured energy landscapes of Trp75 conformations and simulated substrate passage within channel 2b using bufuralol as a model substrate. Trp75 alternated between multiple stable states that supported substrate transport along channel 2b with low-energy barriers between states (∼ -1 kcal/mol). Trp75 conformations were stabilized primarily by hydrogen bonding between Trp75 and Glu222, Asn226, Ala225, or Gln72. Energy barriers were low between Trp75 conformations, allowing Trp75 to easily move between various conformations over time and to function in both binding to and moving substrates in the 2b channel of CYP2D6. Michaelis-Menten kinetic studies completed with purified enzyme in a reconstituted system showed overall reduced enzyme efficiency for metabolism of bufuralol and dextromethorphan by the Trp75Ala mutant compared with CYP2D6*1. In stopped-flow measurements, k off for dextromethorphan was decreased in the absence of Trp75. Our results support a role for Trp75 in substrate shuttling to the active site of CYP2D6. SIGNIFICANCE STATEMENT: Using combined molecular dynamics and in vitro assays, this study shows for the first time a role for Trp75 as a channel entrance gating residue in the mechanism of substrate binding/unbinding in CYP2D6. Energy landscapes derived from molecular dynamics were used to quantitate the strength of gating, and kinetics assays showed the impact on enzyme efficiency and k off of a Trp75Ala mutation.

Development of a method to determine cytochrome P450 1A2, 2C9, 2D6 and 3A4 activity sheep hepatic microsomes

IntroductionEx vivo studies of human fetal hepatic drug metabolism are uncommon as it requires access to functional liver tissue and therefore raises practical and ethical concerns. Large animal models provide an alternative opportunity to study changes in cytochrome P450 (CYP) activity in the mother and fetus during pregnancy. We aimed to develop methods to determine the activity of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in sheep hepatic microsomes. MethodsWe identified optimal conditions to determine the activity of CYP1A2 (using the probe drug phenacetin), CYP2C9 (diclofenac), CYP2D6 (dextromethorphan) and CYP3A4 (midazolam) by varying techniques for microsome extraction, probe drug concentration, incubation time and microsome concentration. The specificity of each probe drug was assessed by determining the rate of metabolism when specific CYP enzyme inhibitors were included in the reaction. ResultsThe optimum incubation time and probe drug concentration was six hours with 5 μM phenacetin (CYP1A2), four hours with 10 μM diclofenac (CYP2C9), 30 min with 1 μM of midazolam (CYP3A4) and 10 min with 1 μM dextromethorphan (CYP2D6). For both CYP2D6 and CYP3A4 reactions required 20 μg of microsomal protein, whereas for CYP1A2 and CYP2C9, reactions required 40 μg of microsomal protein. Metabolism of phenacetin, dextromethorphan and midazolam was reduced by specific enzyme inhibitors, but the specific CYP2C9 inhibitor sulfaphenazole did not substantially inhibit diclofenac metabolism. DiscussionThis study identifies the optimal conditions for determining CYP activity in maternal sheep hepatic microsomes. In doing so, we have developed a standardised protocol for assessment of microsomal activity of CYP3A4, CYP1A2 and CYP2D6, but we were unable to optimise conditions for assessment of CYP2C9. This approach can be applied to investigate the impact of pregnancy complications on maternal and fetal hepatic drug metabolism.

Antidepressants Moving in Pipeline

Antidepressants Moving in Pipeline

CYP2D6 Allelic Variants *34, *17-2, *17-3, and *53 and a Thr309Ala Mutant Display Altered Kinetics and NADPH Coupling in Metabolism of Bufuralol and Dextromethorphan and Altered Susceptibility to Inactivation by SCH 66712.

Metabolic phenotype can be affected by multiple factors, including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20% of cytochrome P450-mediated drug metabolism but consists of more than 100 known variants; several variants are commonly found in the population, whereas others are quite rare. Four CYP2D6 allelic variants-three with a series of mutations distal to the active site (*34, *17-2, *17-3) and one ultra-metabolizer with mutations near the active site (*53), along with reference *1 and an active site mutant of *1 (Thr309Ala)-were expressed, purified, and studied for interactions with the typical substrates dextromethorphan and bufuralol and the inactivator SCH 66712. We found that *34, *17-2, and *17-3 displayed reduced enzyme activity and NADPH coupling while producing the same metabolites as *1, suggesting a possible role for Arg296 in NADPH coupling. A higher-activity variant, *53, displayed similar NADPH coupling to *1 but was less susceptible to inactivation by SCH 66712. The Thr309Ala mutant showed similar activity to that of *1 but with greatly reduced NADPH coupling. Overall, these results suggest that kinetic and metabolic analysis of individual CYP2D6 variants is required to understand their possible contributions to variable drug response and the complexity of personalized medicine.

Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease.

Nondopaminergic pathways represent potential targets to treat levodopa-induced dyskinesia in Parkinson's disease (PD). This pilot-study (NCT01767129) examined the safety/efficacy of the sigma-1 receptor-agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating levodopa-induced dyskinesia. PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg twice daily)/placebo in two 2-week double-blind, crossover treatment periods, with intervening 2-week washout. After 14 days, a 2-hour intravenous levodopa-infusion was administered. Patient examinations were videotaped before infusion ("off" state) and every 30 minutes during and afterwards until patients returned to "off." The primary endpoint was dyskinesia-severity during infusion measured by Unified Dyskinesia Rating Scale part 3 area-under-curve scores (blinded expert rated). Additional endpoints included other dyskinesia/motor assessments, global measures of clinical-change, and adverse-events. A total of 13 patients were randomized and completed the study (efficacy-evaluable population). Dyskinesia-severity was nonsignificantly lower with dextromethorphan/quinidine than placebo during infusion (area-under-curve 966.5 vs 1048.8; P = .191 [efficacy-evaluable patients]), and significantly lower in a post-hoc sensitivity analysis of the per-protocol-population (efficacy-evaluable patients with ≥ 80% study-drug-compliance, n = 12) when measured from infusion start to 4-hours post-infusion completion (area-under-curve 1585.0 vs 1911.3; P = .024). Mean peak dyskinesia decreased significantly from infusion-start to return to "off" (13.3 vs 14.9; P = .018 [efficacy-evaluable patients]). A total of 9 patients rated dyskinesia "much/very much improved" on dextromethorphan/quinidine versus 1-patient on placebo. Dextromethorphan/quinidine did not worsen PD-motor scores, was generally well tolerated, and was associated with more frequent adverse events. This study provides preliminary evidence of clinical benefit with dextromethorphan/quinidine for treating levodopa-induced dyskinesia in PD. Larger studies with a longer treatment duration need to corroborate these early findings. © 2017 International Parkinson and Movement Disorder Society.

Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms.

This study focused on the role of cytochrome P450 2D6 (CYP2D6) genotypes to predict phenotypes in the metabolism of dextromethorphan. CYP2D6 genotypes and metabolic ratios (MRs) of dextromethorphan were determined in 201 Koreans. Unsupervised clustering algorithms, hierarchical and k-means clustering analysis, and color visualizations of CYP2D6 activity were performed on a subset of 130 subjects. A total of 23 different genotypes were identified, five of which were observed in one subject. Phenotype classifications were based on the means, medians, and standard deviations of the log MR values for each genotype. Color visualization was used to display the mean and median of each genotype as different color intensities. Cutoff values were determined using receiver operating characteristic curves from the k-means analysis, and the data were validated in the remaining subset of 71 subjects. Using the two highest silhouette values, the selected numbers of clusters were three (the best) and four. The findings from the two clustering algorithms were similar to those of other studies, classifying *5/*5 as a lowest activity group and genotypes containing duplicated alleles (i.e., CYP2D6*1/*2N) as a highest activity group. The validation of the k-means clustering results with data from the 71 subjects revealed relatively high concordance rates: 92.8% and 73.9% in three and four clusters, respectively. Additionally, color visualization allowed for rapid interpretation of results. Although the clustering approach to predict CYP2D6 phenotype from CYP2D6 genotype is not fully complete, it provides general information about the genotype to phenotype relationship, including rare genotypes with only one subject.

Dextromethorphan and debrisoquine metabolism and polymorphism of the gene for cytochrome P450 isozyme 2D50 in Thoroughbreds.

OBJECTIVE To characterize polymorphisms of the gene for cytochrome P450 isozyme 2D50 (CYP2D50) and the disposition of 2 CYP2D50 probe drugs, dextromethorphan and debrisoquine, in horses. ANIMALS 23 healthy horses (22 Thoroughbreds and 1 Standardbred). PROCEDURES Single-nucleotide polymorphisms (SNPs) in CYP2D50 were identified. Disposition of dextromethorphan (2 mg/kg) and debrisoquine (0.2 mg/kg) were determined after oral (dextromethorphan) or nasogastric (debrisoquine) administration to the horses. Metabolic ratios of plasma dextromethorphan and total dextrorphan (dextrorphan plus dextrorphan-O-β-glucuronide) and 4-hydroxydebrisoquine concentrations were calculated on the basis of the area under the plasma concentration-versus-time curve extrapolated to infinity for the parent drug divided by that for the corresponding metabolite. Pharmacokinetic data were used to categorize horses into the phenotypic drug-metabolism categories poor, extensive, and ultrarapid. Disposition patterns were compared among categories, and relationships between SNPs and metabolism categories were explored. RESULTS Gene sequencing identified 51 SNPs, including 27 nonsynonymous SNPs. Debrisoquine was minimally detected after oral administration. Disposition of dextromethorphan varied markedly among horses. Metabolic ratios for dextromethorphan ranged from 0.03 to 0.46 (mean, 0.12). On the basis of these data, 1 horse was characterized as a poor metabolizer, 18 were characterized as extensive metabolizers, and 3 were characterized as ultrarapid metabolizers. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that CYP2D50 is polymorphic and that the disposition of the probe drug varies markedly in horses. The polymorphisms may be related to rates of drug metabolism. Additional research involving more horses of various breeds is needed to fully explore the functional implication of polymorphisms in CYP2D50.

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.

Modulation of the pentose phosphate pathway alters phase I metabolism of testosterone and dextromethorphan in HepG2 cells.

The pentose phosphate pathway (PPP) is involved in the activity of glucose-6-phosphate dehydrogenase (G6PD) and generation of NADPH, which plays a key role in drug metabolism. The aim of this study was to investigate the effects of modulation of the PPP on drug metabolism capacity in vitro. A pair of hepatic cell lines, ie, the cancerous HepG2 cells and normal L02 cells, was used. The expression of CYP450 enzymes, p53 and G6PD in the cells were analyzed. The metabolism of testosterone (TEST, 10 μmol/L) and dextromethorphan (DEM, 1 μmol/L), the two typical substrates for CYP3A4 and CYP2D6, in the cells was examined in the presence of different agents. Both the expression and metabolic activities of CYP3A4 and CYP2D6 were considerably higher in HepG2 cells than in L02 cells. The metabolism of TEST and DEM in HepG2 cells was dose-dependently inhibited by the specific CYP3A4 inhibitor ketoconazole and CYP2D6 inhibitor quinidine. Addition of the p53 inhibitor cyclic PFT-α (5, 25 μmol/L) in HepG2 cells dose-dependently enhanced the metabolism of DEM and TEST, whereas addition of the p53 activator NSC 66811 (3, 10, 25 μmol/L) dose-dependently inhibited the metabolism. Furthermore, addition of the G6PD inhibitor 6-aminonicotinamide (5, 15 μmol/L) in HepG2 cells dose-dependently inhibited the metabolism of DEM and TEST, whereas addition of the PPP activity stimulator menadione (1, 5, 15 μmol/L) dose-dependently enhanced the metabolism. Modulation of p53 and the PPP alters the metabolism of DEM and TEST, suggesting that the metabolic flux pattern of PPP may be closely involved in drug metabolism and the individual variance.

Dextromethorphan/quinidine: a review of its use in adults with pseudobulbar affect.

Fixed-dose dextromethorphan/quinidine capsules (Nuedexta(®)) utilize quinidine to inhibit the metabolism of dextromethorphan, enabling high plasma dextromethorphan concentrations to be reached without using a larger dose of the drug. The drug combination is the first treatment to be approved for pseudobulbar affect (PBA), a condition of contextually inappropriate/exaggerated emotional expression that often occurs in adults with neurological damage conditions, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, traumatic brain injury, Alzheimer's disease or Parkinson's disease. Dextromethorphan/quinidine at the recommended dosages of 20/10 or 30/10mg twice daily reduced the rate of PBA episodes and improved PBA severity in a 12-week, double-blind, placebo-controlled trial in adults with ALS or MS (STAR), with further improvements in the severity of the condition observed in a 12-week open-label extension phase. Dextromethorphan/quinidine 20/10mg twice daily also improved PBA secondary to dementia in a cohort of a 12-week noncomparative trial (PRISM II). The drug combination was generally well tolerated in these studies, with no particular safety or tolerability concerns. Although longer-term efficacy and tolerability data for dextromethorphan/quinidine 20/10 or 30/10mg twice daily would be beneficial, current evidence indicates that it is a useful option in the treatment of adults with PBA.

Effect of Crude Extract of Eugenia jambolana Lam. on Human Cytochrome P450 Enzymes

The fruit of Eugenia jambolana Lam. is very popular for its anti-diabetic property. Previous studies on the crude extract of E. jambolana (EJE) have successfully explored the scientific basis for some of its traditional medicinal uses. Considering its wide use and consumption as a seasonal fruit, the present study investigates the ability of E. jambolana to interact with cytochrome P450 enzymes. The standardized EJE was incubated with pooled human liver microsomes to assess the CYP2C9-, CYP2D6-, and CYP3A4-mediated metabolism of diclofenac, dextromethorphan, and testosterone, respectively. The metabolites formed after the enzymatic reactions were quantified by high performance liquid chromatography. EJE showed differential effect on cytochrome P450 activities with an order of inhibitory potential as CYP2C9 > CYP3A4 > CYP2D6 having IC50 of 76.69, 359.02, and 493.05 µg/mL, respectively. The selectivity of EJE for CYP2C9 rather than CYP3A4 and CYP2D6 led to perform the enzyme kinetics to explicate the mechanism underlying the inhibition of CYP2C9-mediated diclofenac 4'-hydroxylation. EJE was notably potent in inhibiting the reaction in a non-competitive manner with Ki of 84.85 ± 5.27 µg/mL. The results revealed the CYP2C9 inhibitory potential of EJE with lower Ki value suggesting that EJE should be examined for its potential pharmacokinetic and pharmacodynamic interactions when concomitantly administered with other drugs.

Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects

Effect of Curcuma longa rhizome powder and its ethanolic extract on CYP2D6 and CYP3A4 metabolic activity was investigated in vitro using human liver microsomes and clinically in healthy human subjects. Dextromethorphan (DEX) was used as common probe for CYP2D6 and CYP3A4 enzymes. Metabolic activity of CYP2D6 and CYP3A4 was evaluated through in vitro study; where microsomes were incubated with NADPH in presence and absence of Curcuma extract. In clinical study phase-I, six healthy human subjects received a single dose (30 mg) of DEX syrup, and in phase-II DEX syrup was administered with Curcuma powder. The enzyme CYP2D6 and CYP3A4 mediated O- and N-demethylation of dextromethorphan into dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Curcuma extract significantly inhibited the formation of DOR and 3-MM, in a dose-dependent and linear fashion. The 100 μg/ml dose of curcuma extract produced highest inhibition, which was about 70 % for DOR and 80 % for 3-MM. Curcuma significantly increases the urine metabolic ratio of DEX/DOR but the change in DEX/3-MM ratio was statistically insignificant. Present findings suggested that curcuma significantly inhibits the activity of CYP2D6 in in vitro as well as in vivo; which indicates that curcuma has potential to interact with CYP2D6 substrates.

Concentration-dependent inhibitory effects of baicalin on the metabolism of dextromethorphan, a dual probe of CYP2D and CYP3A, in rats

Baicalin has been shown to possess many pharmacological effects, including antiviral, antioxidant, anti-cancer and anti-inflammatory properties. In the current study, we reveal the inhibitory effects of baicalin on the metabolism of dextromethorphan (DXM), a dual probe substrate of CYP2D and CYP3A, in rats. Lineweaver–Burk plots demonstrated that baicalin inhibited the activities of CYP2D and CYP3A in a non-competitive manner in rat liver microsomes (RLMs). Concomitant administration of baicalin (0.90g/kg, i.v.) and DXM (10mg/kg, i.v.) increased the maximum drug concentration (Cmax) (37%) and the area under concentration–time curve (AUC) (42%) and decreased the clearance (CL) (27%) of DXM in a randomised, crossover study in rats (P<0.01). The change in the AUC of DXM was significantly correlated with the Cmax and AUC of baicalin (P<0.05). The inhibitory effects of multiple doses of baicalin (0.90g/kg, i.v., 12days) on the metabolism of DXM were similar to those observed following a single dose in rats. The activity of CYP3A in excised liver samples from rats following multiple baicalin treatment was significantly decreased compared to that of the control group (P<0.05), whereas multiple doses of baicalin had no obvious effect on the activity of CYP2D. Taken together, these data demonstrate that baicalin inhibits the metabolism of DXM in a concentration-dependent manner in rats, possibly through inhibiting hepatic CYP2D and CYP3A activities.

CYP2D6 phenotype indicative for optimized antiestrogen efficacy associates with outcome in early breast cancer patients

Endoxifen serum concentrations seem to correlate with outcome in breast cancer (BC) patients. Concurrently, cytochrome P450 2D6 (CYP2D6) enzyme activity and dextromethorphan (DM) metabolism are deemed a surrogate marker for the formation of endoxifen. Here, we conducted a matched cohort study to determine the impact of an extensive CYP2D6 phenotype on relapse in patients with early-stage estrogen receptor (ER)-positive BC and adjuvant tamoxifen intake. CYP2D6 extensive metabolism was determined upon appropriate dextromethorphan/dextrorphan (DM/DX) urinary excretion ratios (≤0.30). Fifty-nine BC patients were identified as extensive phenotype metabolizers, while for 148 matched controls, CYP2D6 was not determined. Patients and controls did not differ with respect to age, stage, hormone receptor status, HER2, grade, menopausal status, chemotherapy and antihormonal therapy. Survival analysis was performed according to clinical follow-up. Disease-free survival (DFS) of patients identified as extensive CYP2D6 metabolizers did not differ significantly from controls (p = 0.10). However, when patients with ER expression of ≤ 20 % were excluded from the analysis, DFS was associated with a more favorable outcome (p = 0.06). This study suggests a positive association between extensive CYP2D6 metabolism and outcome in early-stage ER-positive BC patients using tamoxifen and in particular, when a sufficient number ERs are represented on the primary tumor.

Polysaccharide peptides from Coriolus versicolor competitively inhibit model cytochrome P450 enzyme probe substrates metabolism in human liver microsomes

Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy or health supplement in China. Previous studies have shown that PSP decreased antipyrine clearance and inhibited rat CYP2C11-mediated tolbutamide 4-hydroxylation and in human CYP2C9. In this study, the effects of the water extractable fraction of PSP on the metabolism of model CYP1A2, CYP2D6, CYP2E1 and CYP3A4 probe substrates were investigated in pooled human liver microsomes. PSP (1.25–20μM) dose-dependently decreased CYP1A2-mediated metabolism of phenacetin to paracetamol (IC50 19.7μM) and CYP3A4-mediated metabolism of testosterone to 6β-hydroxytestosterone (IC20 7.06μM). Enzyme kinetics studies showed the inhibition of CYP1A2 activity was competitive and concentration-dependent (Ki=18.4μM). Inhibition of testosterone to 6β-hydroxytestosterone was also competitive and concentration-dependent (Ki=31.8μM). Metabolism of dextromethorphan to dextrorphan (CYP2D6-mediated) and chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1-mediated) was only minimally inhibited by PSP, with IC20 values at 15.6μM and 11.9μM, respectively. This study demonstrated that PSP competitively inhibited the CYP1A2- and CYP3A4-mediated metabolism of model probe substrates in human liver microsomes in vitro. The relatively high Ki values for CYP1A2 and CYP3A4 would suggest a low potential for PSP to cause herb–drug interaction related to these CYP isoforms.