Prediction of the drug-drug interaction potential of the α1-acid glycoprotein bound, CYP3A4/CYP2C9 metabolized oncology drug, erdafitinib.

Erdafitinib is a potent oral pan-fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1-acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug-drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time-dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor-metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P-glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.

Effect of GLPG1205, a GPR84 Modulator, on CYP2C9, CYP2C19, and CYP1A2 Enzymes: In Vitro and Phase 1 Studies.

GLPG1205 is a novel agent being investigated for the treatment of idiopathic pulmonary fibrosis. GLPG1205 may be concomitantly administered with pirfenidone in future clinical development; therefore, the potential for GLPG1205 to interact with enzymes involved in the metabolism of pirfenidone (cytochrome P450 [CYP] 1A2, CYP2C9, 2C19) was evaluated. In vitro experiments indicated weak inhibition of CYP1A2 and moderate but reversible inhibition of CYP2C9 and CYP2C19 by GLPG1205. A phase 1 randomized, double-blind crossover study in 14 healthy males (NCT02623296) evaluated the effect of GLPG1205 100 mg or placebo (once daily for 12 days) on the single-dose pharmacokinetics of a cocktail of CYP1A2, CYP2C9, and CYP2C19 substrates (coadministered on day 13). GLPG1205 had no effect on the exposure of CYP2C9 and CYP1A2 substrates or metabolites; however, a trend toward increased omeprazole (CYP2C19 substrate) exposure was observed. Although considered not clinically relevant, GLPG1205 increased the elimination rate of 5-hydroxyomeprazole (CYP2C19 metabolite) 1.16-fold versus placebo. GLPG1205 had no effect on the elimination of all other substrates or metabolites. GLPG1205 had a favorable safety and tolerability profile. In conclusion, GLPG1205 100 mg once daily does not interact with CYP2C9, CYP2C19, or CYP1A2 to a clinically relevant extent and may be administered concomitantly with drugs metabolized by these enzymes.

Pogostone inhibits the activity of CYP3A4, 2C9, and 2E1 in vitro.

CONTEXT: Pogostone possesses various pharmacological activities, which makes it widely used in the clinic. Its effect on the activity of cytochrome P450 enzymes (CYP450s) could guide its clinical combination. OBJECTIVE: To investigate the effect of pogostone on the activity of human CYP450s. MATERIALS AND METHODS: The effect of pogostone on the activity of CYP450s was evaluated in human liver microsomes (HLMs) compared with blank HLMs (negative control) and specific inhibitors (positive control). The corresponding parameters were obtained with 0-100 µM pogostone and various concentrations of substrates. RESULTS: Pogostone was found to inhibit the activity of CYP3A4, 2C9, and 2E1 with the IC50 values of 11.41, 12.11, and 14.90 µM, respectively. The inhibition of CYP3A4 by pogostone was revealed to be performed in a non-competitive and time-dependent manner with the Ki value of 5.69 µM and the KI/Kinact value of 5.86/0.056/(µM/min). For the inhibition of CYP2C9 and 2E1, pogostone acted as a competitive inhibitor with the Ki value of 6.46 and 7.67 µM and was not affected by the incubation time. DISCUSSION AND CONCLUSIONS: The inhibitory effect of pogostone on the activity of CYP3A4, 2C9, and 2E1 has been disclosed in this study, implying the potential risk during the co-administration of pogostone and drugs metabolized by these CYP450s. The study design provides a reference for further in vivo investigations to validate the potential interaction.

The inhibition of CYP1A2, CYP2C9, and CYP2D6 by pterostilbene in human liver microsomes.

This study used human liver microsomes to assess pterostilbene's effect on the metabolic activity of cytochrome P450 (CYP) 1A2, CYP2C9, and CYP2D6. The metabolism of their substrates (phenacetin, tolbutamide, and dextromethorphan) was assayed by quantifying their relevant metabolites by HPLC. The IC50 value was used to express the strength of inhibition, and the value of a volume per dose index (VDI) was used to indicate the metabolic ability of the enzyme. In this study, pterostilbene inhibited CYP1A2, CYP2C9, and CYP2D6's metabolic activities in vitro. CYP2C9's activity was most significantly inhibited by pterostilbene; its IC50 value was 0.12±0.04 µM. The IC50 value of CYP1A2 and CYP2D6 was 56.3±10.4 µM and 62.33±11.4 µM, respectively. The finding that suggests that pterostilbene has the potential to interact with CYP2C9 substrates in vivo. These results warrant clinical studies to assess the in vivo significance of these interactions.

Evaluation of Potential Drug-Drug Interaction Risk of Pexidartinib With Substrates of Cytochrome P450 and P-Glycoprotein.

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Herein, 2 open-label, single-sequence, crossover studies evaluated the drug-drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P-gp. Thirty-two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P-gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates' pharmacokinetics. No drug-drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast ) of midazolam, whereas AUClast values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite-to-parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19-mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUClast . These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19-mediated metabolism or P-gp transport.

Clinical analysis of the effects of azole antifungal agents on the anticoagulant activity of warfarin.

To investigate the frequency and degree of azole antifungal agents that influence the anticoagulant activity of warfarin to reduce the potential bleeding risk and provide a reference for rational administration of warfarin in clinics.Patients with an abnormal international normalized ratio (INR; INR ≥ 4.5) and treated with warfarin plus azole antifungal agents were screened from February 2011 to July 2016, and their data were extracted.Thirty-two patients treated with warfarin plus azole antifungal agents were included. The INR of all the included patients increased by more than 20% of the INR of warfarin alone, and the warfarin sensitivity index showed an upward trend. The INRs of 21 patients treated with fluconazole (FLCZ) and warfarin was closely monitored for 1 week after the combination treatment, and the interaction between warfarin and the azole antifungal agents peaked on the seventh day. The INRs when warfarin was coadministered with azoles (Y) correlated significantly with those in the absence of azoles (X): FLCZ: Y = 1.2515X + 2.1538, R = 0.8128; and voriconazole Y = 2.4144 X + 2.6216, R2 = 0.7828.The combination of FLCZ and voriconazole will enhance the anticoagulant effect of warfarin. Therefore, it is recommended to detect the genotype of CYP2C9 in patients and evaluate the interaction between the 2 drugs to adjust the warfarin dose. It is also recommended to closely monitor INR within 1 week of the addition of azole antifungal agents.

Clinical Pharmacokinetics and Pharmacodynamics of Etravirine: An Updated Review.

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of human immunodeficiency virus type 1 infection. It is a potent inhibitor of HIV reverse transcriptase and retains activity against wild-type and most NNRTI-resistant HIV. The pharmacokinetic profile of etravirine and clinical data support twice-daily dosing, although once-daily dosing has been investigated in treatment-naïve and treatment-experienced persons. Despite similar pharmacokinetic and pharmacodynamic results compared with twice-daily dosing, larger studies are needed to fully support once-daily etravirine dosing in treatment-naïve individuals. Etravirine is reserved for use in third- or fourth-line antiretroviral treatment regimens, as recommended, for example, in treatment guidelines by the US Department of Health and Human Services-Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Etravirine exhibits the potential for bi-directional drug-drug interactions with other antiretrovirals and concomitant medications through its interactions with cytochrome P450 (CYP) isozymes: CYP3A4, CYP2C9, and CYP2C19. This review summarizes the pharmacokinetic and pharmacodynamic parameters of etravirine, with particular attention to information on drug-drug interactions and use in special patient populations, including children/adolescents, women, persons with organ dysfunction, and during pregnancy.

CYP2C9-mediated warfarin and milk thistle interaction.

WHAT IS KNOWN AND OBJECTIVE: In vitro studies suggest a CYP2C9-mediated interaction between milk thistle and warfarin, but there has been no in vivo case report on this interaction. CASE DESCRIPTION: A White Hispanic man in his 30s was well controlled on warfarin therapy for mitral valve replacement. His INR increased from 2.64 to 4.12, and he denied changes to his medications and diet but noted starting a 'liver cleanse' supplement which contained milk thistle (200 mg). After stopping the supplement his INR normalized, and he remains on the same warfarin dose. WHAT IS NEW AND CONCLUSION: This is the first in vivo report of an interaction between milk thistle and warfarin.

An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes.

Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an important role in predicting the occurrence of adverse effects and the efficacy of substrate medications. Drug-induced changes to the enzyme's phenotype, a process called phenoconversion, comprise another important factor contributing to interindividual variability in drug response. To date, there is lack of data on the frequency of these common polymorphisms and phenoconversion in the pan-ethnic Australian population. The aim of this study was to (1) describe allele, genotype and phenotype frequencies for CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes in the pan-ethnic Australian population and (2) evaluate the frequency of actionable pharmacogenomic (PGx) variants and phenoconversion. Frequencies were calculated using the records of 5408 Australian patients (obtained from myDNA's propriety database), who were consecutively tested with the DNAdose PGx test which included the CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. In 2509 patients with listed medications at the time of testing, phenoconversion frequencies were calculated for CYP2D6, CYP2C19 and CYP2C9 enzymes. Allele, genotype and phenotype frequencies in our Australian patients correlated with a Caucasian population. Approximately 96% of patients had at least one actionable PGx variant. A five-fold increase in the frequency of poor metabolisers (PMs) for CYP2D6 and CYP2C19 was predicted by phenoconversion. Our study results indicate a high frequency of actionable PGx variants in our Australian population. With the addition of drug-induced phenoconversion, our results provide further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine.

Effects of rolapitant administered orally on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects.

PURPOSE: Rolapitant is a neurokinin-1 receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed chemotherapy-induced nausea and vomiting. We evaluated the effects of rolapitant oral on the pharmacokinetics of probe substrates for cytochrome P450 (CYP) 2D6 (dextromethorphan), 2C9 (tolbutamide), 2C19 (omeprazole), 2B6 (efavirenz), and 2C8 (repaglinide) in healthy subjects. METHODS: This open-label, multipart, randomized, phase 1 study assessed cohorts of 20-26 healthy subjects administered dextromethorphan, tolbutamide plus omeprazole, efavirenz, or repaglinide with and without single, oral doses of rolapitant. Maximum plasma analyte concentrations (Cmax) and area under the plasma analyte concentration-time curves (AUC) were estimated using noncompartmental analysis, and geometric mean ratios (GMRs) and 90% confidence intervals for the ratios of test (rolapitant plus probe substrate) to reference (probe substrate alone) treatment were calculated. RESULTS: Rolapitant significantly increased the systemic exposure of dextromethorphan in terms of Cmax and AUC0-inf by 2.2- to 3.3-fold as observed in GMRs on days 7 and 14. Rolapitant did not affect systemic exposure of tolbutamide, and minor excursions outside of the 80-125% no effect limits were detected for omeprazole, efavirenz, and repaglinide. CONCLUSIONS: Inhibition of dextromethorphan by a single oral dose of rolapitant 180 mg is clinically significant and can last at least 7 days. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6, or CYP2C8. CYP2D6 substrate drugs with a narrow therapeutic index may require monitoring for adverse reactions if given concomitantly with rolapitant.

Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects.

OBJECTIVES: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). METHODS: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies. CONCLUSIONS: Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.

Effect of Naltrexone Hydrochloride on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activity in Human Liver Microsomes.

BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. METHODS: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, dextromethorphan O-demethylation, and testosterone 6ß-hydroxylation reactions were monitored for enzyme activity. RESULTS: The activity of all the studied CYP enzymes except 1A2 was significantly inhibited by naltrexone hydrochloride 1 µM. Furthermore, 1 µM naltrexone hydrochloride inhibited CYP3A4 enzyme activity, the most by 37.9% followed by CYP2C9 (36.5%) and CYP2D6 (31.8%). The CYP2C9 and CYP2D6 metabolic activities were greatly affected by naltrexone hydrochloride, which even at the lowest concentration of naltrexone hydrochloride (0.01 µM) significantly decreased the metabolic activity by 34.9 and 16.0%, respectively. The half maximal inhibition concentration (IC50) values for CYP2C9 and CYP2D6 inhibition were 3.40 ± 1.78 and 5.92 ± 1.58 µM, respectively. CONCLUSION: These outcomes advocate that there is a great possibility of drug interactions resulting from the concurrent administration of naltrexone hydrochloride with actives that are metabolized by these CYP enzymes, particularly CYP2C9 and CYP2D6. Nevertheless, further clarification is needed through detailed in vivo pharmacokinetic studies.

Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro.

AIM: The aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin. METHODS: We performed an open-label, randomized, two-phase, five-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays. RESULTS: A total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0 to 24 h for omeprazole (CYP2C19) {geometric mean ratio [GMR] [95% confidence interval (CI)]: 0.33 [0.24, 0.45]}, tolbutamide (CYP2C9) [GMR (95% CI): 0.73 (0.65, 0.81)] and midazolam (CYP3A4) [GMR (95% CI): 0.54 (0.41, 0.72)]. Additionally, other relevant pharmacokinetic parameters were affected, indicating the induction of CYP2C- and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose-dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the pregnane X receptor. CONCLUSIONS: Dicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism, and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.

An S-warfarin and AZD1981 interaction: in vitro and clinical pilot data suggest the N-deacetylated amino acid metabolite as the primary perpetrator.

AIM: AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug-drug interaction (DDI) and on a clinical warfarin DDI study. The aim was to demonstrate that N-deacetylated AZD1981 is responsible for the observed interaction. METHODS: The excretion and biotransformation of [14 C]-AZD1981 were studied in healthy male volunteers, and subsequently in vitro cytochrome P450 (CYP) inhibition and hepatocyte uptake investigations were carried out with metabolites and the parent drug. A clinical DDI study using coadministered twice-daily 100 mg and 400 mg AZD1981 with 25 mg warfarin was performed. RESULTS: The excretion balance study showed N-deacetylated AZD1981 to be the most abundant metabolite present in plasma. In vitro data revealed the metabolite to be a weak CYP2C9 time-dependent inhibitor, subject to more active hepatic uptake than the parent molecule. Clinically, the S-warfarin area under the plasma concentration-time curve increased, on average, 1.4-fold [95% confidence interval (CI) 1.22, 1.50] and 2.4-fold (95% CI 2.11, 2.64) after 100 mg (n = 13) and 400 mg (n = 11) AZD1981 administration, respectively. In vitro CYP inhibition and hepatocyte uptake data were used to explain the interaction. CONCLUSIONS: N-deacetylated AZD1981 can be added to the small list of drug metabolites reported as sole contributors to clinical drug-drug interactions, with weak time-dependent inhibition exacerbated by efficient hepatic uptake being the cause.

African Lettuce (Launaea taraxacifolia) Displays Possible Anticancer Effects and Herb-Drug Interaction Potential by CYP1A2, CYP2C9, and CYP2C19 Inhibition.

Medicinal plants are part of the healthcare systems worldwide, especially in low- and middle-income countries. African lettuce (Launaea taraxacifolia) is cultivated extensively in Africa, from Senegal in the west to Ethiopia and Tanzania in the east, and in Southern Africa. Potential anticancer effects of L. taraxacifolia have been suggested, but little is known about putative molecular mechanisms or potential for herb-drug interactions through inhibition or induction of drug-metabolizing enzymes. We investigated the effects of crude aqueous extracts of L. taraxacifolia on growth kinetics and cell cycle progression of the WHC01 esophageal cancer cells. Antiproliferative and apoptotic effects were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometry, while examining, in parallel, the genes regulating apoptosis and cell cycle in this cell culture model. In addition, we tested the inhibitory and enzyme kinetic effects of the aqueous L. taraxacifolia using recombinant human CYP450 isozyme model systems (CYP1A2, CYP2C9, and CYP2C19). L. taraxacifolia exhibited a significant growth inhibitory effect on the WHC01 cancer cells. Most cell cycle genes were downregulated. Cell cycle analysis showed a G0-G1 cell cycle arrest in WHC01 cells in the presence of L. taraxacifolia extract, accompanied by morphological changes. L. taraxacifolia extract treatment resulted in downregulation of expression levels of CYP1A2 (p < 0.0005) and CYP2C19 (p < 0.003) by 50-70%. L. taraxacifolia extract caused reversible and time-dependent inhibition of the recombinant CYP1A2, CYP2C9, and CYP2C19. This study provides new insights on possible anticancer effects of L. taraxacifolia, a widely used medicinal plant in parts of Africa and across the world especially by patients with cancer. Further mechanistic studies expanding on these observations would be timely and contribute to the field of global precision medicine that requires solid understanding of drug and herb molecular mechanisms of action and drug-herb interaction potentials, given the worldwide use of medicinal plants.

Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. RESULTS: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. CONCLUSIONS: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

Three Serious Drug Interactions that Every Dentist Should Know About.

Patients with complex medical and drug histories are becoming more commonplace in dental practice. This article reviews three serious adverse drug interactions that are well supported by the literature and can impact dental practice. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the renal excretion of lithium and lead to lithium toxicity. Metronidazole and fluconazole inhibit the metabolism of warfarin by blocking cytochrome P-450 2C9 (CYP-2C9), the major metabolic pathway of warfarin, with the end result being dramatic increases in patients' international normalized ratios (INRs) and potentially fatal bleeding. Propranolol and other nonselective beta-adrenergic blocking agents can inhibit the vasodilatory effect of epinephrine in dental local anesthetic solutions, leading to hypertensive reactions and a concomitant reflex bradycardia. It is important for clinicians to recognize and avoid these serious drug interactions. By doing so, they will provide the safest and best treatment for their patients.

Combination of capecitabine and phenytoin may cause phenytoin intoxication: a case report.

Capecitabine is an oral antineoplastic agent, and phenytoin is an anticonvulsant drug with a narrow therapeutic index. Although the interaction between capecitabine and phenytoin is rare, it may be potentially fatal. This interaction is thought to be at the level of CYP2C9 isoenzyme system in the liver. Here, we present a patient with metastatic breast cancer who developed phenytoin intoxication when using capecitabine and phenytoin together. Closely monitoring plasma phenytoin levels is essential if capecitabine is used with phenytoin concurrently.