RESUMO
Pritelivir is a novel viral helicase-primase inhibitor active against herpes simplex virus. In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Feminino , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Masculino , Adulto , Bupropiona/farmacologia , Bupropiona/farmacocinética , Sulfonamidas/farmacologia , Pessoa de Meia-Idade , Rosuvastatina Cálcica/farmacologia , Rosuvastatina Cálcica/farmacocinética , Flurbiprofeno/farmacologia , Flurbiprofeno/farmacocinética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Carbamatos/farmacologia , Midazolam/farmacocinética , Midazolam/farmacologia , Adulto Jovem , Piperidinas/farmacologia , Piperidinas/farmacocinéticaRESUMO
OBJECTIVE: Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling. ANIMALS: 12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019. METHODS: In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine. RESULTS: The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios. CONCLUSIONS: The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs. CLINICAL RELEVANCE: The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.
Assuntos
Bupropiona , Estudos Cross-Over , Dextrometorfano , Omeprazol , Animais , Cães , Dextrometorfano/farmacocinética , Dextrometorfano/urina , Dextrometorfano/metabolismo , Bupropiona/farmacocinética , Bupropiona/metabolismo , Bupropiona/sangue , Omeprazol/farmacocinética , Feminino , Masculino , Sistema Enzimático do Citocromo P-450/metabolismo , Fenótipo , Hidrocarboneto de Aril Hidroxilases/metabolismoRESUMO
Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.
Assuntos
Bupropiona , Bupropiona/análogos & derivados , Transtorno Depressivo Maior , Humanos , Bupropiona/farmacocinética , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C19 , Farmacogenética , Estudos Cross-Over , Estudos Prospectivos , Sistema Enzimático do Citocromo P-450/genética , Obesidade , Oxirredutases N-Desmetilantes/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. METHODS: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. RESULTS: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. CONCLUSION: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
Assuntos
Bupropiona , Carbamatos , Coproporfirinas , Interações Medicamentosas , Inibidores de Hidroximetilglutaril-CoA Redutases , Rosuvastatina Cálcica , Sulfonamidas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Bupropiona/administração & dosagem , Bupropiona/farmacocinética , Carbamatos/administração & dosagem , Carbamatos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Idoso de 80 Anos ou maisRESUMO
PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.
Assuntos
Bupropiona , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Interações Medicamentosas , Midazolam , Estaurosporina , Humanos , Área Sob a Curva , Bupropiona/farmacocinética , Bupropiona/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Anticoncepcionais Orais/farmacologia , Anticoncepcionais Orais/farmacocinética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Combinação de Medicamentos , Etinilestradiol/farmacocinética , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacologia , Voluntários Saudáveis , Levanogestrel/farmacocinética , Levanogestrel/administração & dosagem , Levanogestrel/farmacologia , Midazolam/farmacocinética , Midazolam/administração & dosagem , Pioglitazona/farmacologia , Pioglitazona/administração & dosagem , Pioglitazona/farmacocinética , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Estaurosporina/farmacocinética , Estaurosporina/administração & dosagem , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Bupropion is an atypical antidepressant and smoking cessation aid; its use is associated with wide intersubject variability in efficacy and safety. Knowledge of the brain pharmacokinetics of bupropion and its pharmacologically active metabolites is considered important for understanding the cause-effect relationships driving this variability. METHODS: Brain concentrations from rats administered a 10 mg/kg subcutaneous dose of racemic bupropion were analyzed using a stereoselective LC/MS-MS method. A 2 mg/kg dose of (S,S)-hydroxybupropion, which has comparable pharmacologic potency to bupropion, was administered to a separate group of rats. Plasma exposure and unbound concentrations in both matrices from companion equilibrium dialysis experiments were determined to assess potential carrier-mediated transport at the blood-brain barrier. RESULTS: Exposures to unbound forms of bupropion enantiomers were similar in plasma; this was also true in brain. This trend held for reductive diastereomer metabolite pairs in the two matrices. Unbound (R,R)-hydroxybupropion exposure was 1.5-fold higher than (S,S)-hydroxybupropion exposure in plasma and brain following bupropion administration. Unbound concentration ratios (Kp,uu) of a given molecular form decreased over time: between 4 and 6 h, these were < 1 for the two bupropion enantiomers, and they were ~ 1 for metabolites that formed. Administration of preformed (S,S)-hydroxybupropion also demonstrated a declining Kp,uu. CONCLUSIONS: The temporal shift in Kp,uu among the different molecular forms provides evidence regarding the operation of carrier-mediated transport and/or within-brain metabolism of bupropion, and, thereby, fresh insight regarding the causes of intersubject variability in the safety and efficacy of bupropion therapy.
Assuntos
Antidepressivos de Segunda Geração , Bupropiona , Ratos , Animais , Bupropiona/farmacocinética , Encéfalo/metabolismo , Espectrometria de Massas em Tandem/métodosRESUMO
Many mothers need to take some medications during breastfeeding, which may carry a risk to breastfed infants. Thus, determining the amount of a drug transferred into breast milk is critical for risk-benefit analysis of breastfeeding. Breast cancer resistance protein (BCRP), an efflux transporter which usually protects the body from environmental and dietary toxins, was reported to be highly expressed in lactating mammary glands. In this study, we developed a mechanistic lactation physiologically based pharmacokinetic (PBPK) modeling approach incorporating BCRP mediated transport kinetics to simulate the concentration-time profiles of five BCRP drug substrates (acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin) in nursing women's plasma and milk. Due to the lack of certain physiological parameters and scaling factors in nursing women, we combine the bottom up and top down PBPK modeling approaches together with literature reported data to optimize and determine a set of parameters that are applicable for all five drugs. The predictive performance of the PBPK models was assessed by comparing predicted pharmacokinetic profiles and the milk-to-plasma (M/P) ratio with clinically reported data. The predicted M/P ratios for acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin were 2.48, 3.70, 3.55, 1.21, and 5.78, which were all within 1.5-fold of the observed values. These PBPK models are useful to predict the PK profiles of those five drugs in the milk for different dosing regimens. Furthermore, the approach proposed in this study will be applicable to predict pharmacokinetics of other transporter substrates in the milk.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Lactação , Leite Humano , Feminino , Humanos , Lactente , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Bupropiona/farmacocinética , Cimetidina/farmacocinética , Ciprofloxacina/farmacocinética , Lactação/metabolismo , Leite Humano/química , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Nitrofurantoína/farmacocinética , Aciclovir/farmacocinéticaRESUMO
Vicagrel, an antiplatelet drug candidate targeting platelet P2Y12 receptor and has finished its phase II clinical trial. The inhibition of six major cytochrome P450 enzymes (P450) (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and six UDP-glucuronosyltransferases (UGT) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) by vicagrel was evaluated using pooled human liver microsomes and specific probe substrates. Physiology-based pharmacokinetic (PBPK) simulation was further applied to predict the in vivo drug-drug interaction (DDI) potential between vicagrel and bupropion as well as S-mephenytoin. The results suggested that vicagrel inhibited CYP2B6 and CYP2C19 potently with apparent IC50 values of 1.6 and 2.0 µM, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of CYP2B6-catalyzed bupropion hydroxylation and noncompetitive inhibition of CYP2C19-mediated S-mephenytoin 4'-hydroxylation with Ki values of 0.19 µM and 1.2 µM, respectively. Vicagrel displayed profound time-dependent inhibition towards CYP2B6 with maximal rate constant of inactivation (kinact) and half-maximal inactivator concentration (KI) values of 0.062 min-1 and 1.52 µM, respectively. No time-dependent inhibition by vicagrel was noted for CYP2C19. For UGT, negligible to moderate inhibition by vicagrel was observed with IC50 values of >50.0, >50.0, 28.2, 8.7, >50.0 and 28.2 µM for UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of UGT1A6-catalyzed N-Acetylserotonin ß-D-glucuronidation with a Ki value of 5.6 µM. No time-dependent inhibition by vicagrel was noted for UGT1A6. PBPK simulation indicated that neither altered AUC nor Cmax of bupropion and S-mephenytoin was observed in the presence of vicagrel. Our study provides inhibitory constants for future DDI prediction between vicagrel and drug substrates of CYP2B6, CYP2C19 and UGT1A6. In addition, our simulation suggests the lack of clinically important DDI between vicagrel and bupropion or S-mephenytoin.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Fenilacetatos/farmacologia , Tiofenos/farmacologia , Bupropiona/administração & dosagem , Bupropiona/farmacocinética , Simulação por Computador , Citocromo P-450 CYP2B6/metabolismo , Inibidores do Citocromo P-450 CYP2B6/administração & dosagem , Inibidores do Citocromo P-450 CYP2B6/farmacologia , Citocromo P-450 CYP2C19/metabolismo , Inibidores do Citocromo P-450 CYP2C19/administração & dosagem , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Glucuronosiltransferase/metabolismo , Humanos , Técnicas In Vitro , Cinética , Mefenitoína/administração & dosagem , Mefenitoína/farmacocinética , Fenilacetatos/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia , Tiofenos/administração & dosagemRESUMO
This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no-effect interval (0.80-1.25). When co-administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC0-last ) GMR (90% CIs) for midazolam was 0.734 (0.647-0.832). When co-administered with cenobamate 200 mg/day, AUC0-last GMRs (90% CI) for midazolam, bupropion, S-warfarin, and omeprazole were 0.277 (0.238-0.323), 0.615 (0.522-0.724), 1.14 (1.10-1.18), and 2.07 (1.44-2.98), respectively. Co-administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co-administration of cenobamate led to omeprazole values which were outside and above the no-effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co-administration of cenobamate with these probes drugs was well-tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose-dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.
Assuntos
Citocromo P-450 CYP3A , Midazolam , Bupropiona/farmacocinética , Carbamatos , Clorofenóis , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Midazolam/farmacocinética , Omeprazol/farmacocinética , Preparações Farmacêuticas , Tetrazóis , Varfarina/farmacocinéticaRESUMO
Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzofuranos/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Naftoquinonas/administração & dosagem , Proteínas de Neoplasias/metabolismo , Administração Oral , Adulto , Benzofuranos/farmacocinética , Bupropiona/administração & dosagem , Bupropiona/farmacocinética , Cafeína/administração & dosagem , Cafeína/farmacocinética , Dextrometorfano/administração & dosagem , Dextrometorfano/farmacocinética , Interações Medicamentosas , Feminino , Flurbiprofeno/administração & dosagem , Flurbiprofeno/farmacocinética , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Midazolam/administração & dosagem , Midazolam/farmacocinética , Naftoquinonas/farmacocinética , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Bupropion (BUP) is a chiral antidepressant and smoking cessation aide with benefits and side effects correlated with parent and active metabolite concentrations. BUP is metabolized by CYP2B6, CYP2C19, and CYP3A4 to hydroxy-BUP (OH-BUP) as well as by 11ß-hydroxysteroid dehydrogenase-1 and aldo-keto reductases to threohydrobupropion (Threo) and erythrohydrobupropion (Erythro), respectively. As pregnancy alters the activity of drug-metabolizing enzymes, the authors hypothesized that BUP metabolism and BUP metabolite concentrations would be altered during pregnancy, potentially affecting the efficacy and safety of BUP in pregnant women. METHODS: Pregnant women (n = 8) taking BUP chronically were enrolled, and steady-state plasma samples and dosing interval urine samples were collected during pregnancy and postpartum. Maternal and umbilical cord venous blood samples were collected at delivery from 3 subjects, and cord blood/maternal plasma concentration ratios were calculated. The concentrations of BUP stereoisomers and their metabolites were measured. Paired t tests were used to compare pharmacokinetic parameters during pregnancy and postpartum. RESULTS: No significant changes were observed in the steady-state plasma concentrations, metabolite to parent ratios, formation clearances, or renal clearance of any of the compounds during pregnancy when compared with postpartum. The umbilical cord venous plasma concentrations of BUP and its metabolites were 30%-60% lower than maternal plasma concentrations. CONCLUSIONS: This study showed that there are no clinically meaningful differences in the stereoselective disposition of BUP or its metabolites during pregnancy, indicating that dose adjustment during pregnancy may not be necessary. The results also showed that the placenta provides a partial barrier for bupropion and its metabolite distribution to the fetus, with possible placental efflux transport of bupropion and its metabolites.
Assuntos
Bupropiona , Placenta , Antidepressivos/metabolismo , Bupropiona/farmacocinética , Feminino , Humanos , Placenta/metabolismo , Período Pós-Parto , GravidezRESUMO
Human liver microsomes (HLM) and human hepatocytes (HH) are important in vitro systems for studies of intrinsic drug clearance (CLint) in the liver. However, the CLint values are often in disagreement for these two systems. Here, we investigated these differences in a side-by-side comparison of drug metabolism in HLM and HH prepared from 15 matched donors. Protein expression and intracellular unbound drug concentration (Kpuu) effects on the CLint were investigated for five prototypical probe substrates (bupropion-CYP2B6, diclofenac-CYP2C9, omeprazole-CYP2C19, bufuralol-CYP2D6, and midazolam-CYP3A4). The samples were donor-matched to compensate for inter-individual variability but still showed systematic differences in CLint. Global proteomics analysis outlined differences in HLM from HH and homogenates of human liver (HL), indicating variable enrichment of ER-localized cytochrome P450 (CYP) enzymes in the HLM preparation. This suggests that the HLM may not equally and accurately capture metabolic capacity for all CYPs. Scaling CLint with CYP amounts and Kpuu could only partly explain the discordance in absolute values of CLint for the five substrates. Nevertheless, scaling with CYP amounts improved the agreement in rank order for the majority of the substrates. Other factors, such as contribution of additional enzymes and variability in the proportions of active and inactive CYP enzymes in HLM and HH, may have to be considered to avoid the use of empirical scaling factors for prediction of drug metabolism.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Hepatócitos/enzimologia , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Bupropiona/farmacocinética , Sistema Enzimático do Citocromo P-450/análise , Diclofenaco/farmacocinética , Etanolaminas/farmacocinética , Eliminação Hepatobiliar , Humanos , Fígado/citologia , Midazolam/farmacocinética , Omeprazol/farmacocinética , Proteoma/análise , ProteômicaRESUMO
This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (Cmax ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUCinf ), 0.78 (0.72-0.85) for hydroxybupropion Cmax , and 0.72 (0.67-0.78) for hydroxybupropion AUCinf when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC0-24 was 641 ± 177 ng·h/mL, and Cmax was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6.
Assuntos
Bupropiona/farmacocinética , Citocromo P-450 CYP2B6/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Inibidores de Janus Quinases/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Bupropiona/administração & dosagem , Bupropiona/análogos & derivados , Bupropiona/sangue , Bupropiona/metabolismo , Citocromo P-450 CYP2B6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6/sangue , Interações Medicamentosas , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-IdadeRESUMO
Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 µg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.
Assuntos
Adenina/análogos & derivados , Anticoncepcionais Orais/administração & dosagem , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/administração & dosagem , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adenina/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Bupropiona/administração & dosagem , Bupropiona/farmacocinética , Anticoncepcionais Orais/farmacocinética , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacocinética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/metabolismo , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Linfoma de Zona Marginal Tipo Células B/sangue , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/metabolismo , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/metabolismoRESUMO
PURPOSE: Bupropion is an antidepressant drug that facilitates weight loss. It is a highly water-soluble drug that needs multiple dosing, so it is considered a potential candidate for oral controlled-release dosage form. The aim of this research was to formulate and evaluate satiety-inducing swellable floating bupropion tablets by direct compression targeting depression associated with eating disorders. Various combinations of natural and semi-synthetic hydrogels were selected to achieve maximum swelling and remaining buoyant in the stomach. This synergistically enhances weight loss by increasing satiety. METHODS: An I-optimal mixture design was conducted to establish the optimal quantitative composition of tablets. Friability, floating lag time, swelling index after 4 and 8 hours, along with the percent of bupropion released at 1 and 8 hours were selected as dependent variables. The optimized formulation was characterized by physicochemical properties, thermal stability, and chemical interaction. In vivo radiographic evaluation of gastric residence besides, the oral bioavailability relative to marketed Wellbutrin® sustained-release tablets were investigated using human volunteers. RESULTS: The optimized formulation (73.3 mg xanthan, 120 mg glucomannan, 8.4 mg tamarind kernel powder, 78.3 mg HPMC K15M) was achieved with the overall desirability equals 0.782. In vivo radiographic study showed that formulation was retained for >8 hours in the stomach. Compared with the marketed BUP tablets, the Cmax was almost the same with a significant increase (p =0.004) for Tmax. CONCLUSION: Using combinations of these hydrogels would be promising gastroretentive delivery systems in the control of bupropion rate release with enhanced floating and swelling features.
Assuntos
Bupropiona/farmacocinética , Administração Oral , Bupropiona/administração & dosagem , Bupropiona/sangue , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Voluntários Saudáveis , Humanos , Masculino , ComprimidosRESUMO
The antidepressant bupropion is stereoselectively metabolized and metabolite enantiomers have differential pharmacologic effects, but steady-state enantiomeric disposition is unknown. Controversy persists about bupropion XL 300 mg generic equivalence to brand product, and whether generics might have different stereoselective disposition leading to enantiomeric non-bioequivalence and, thus, clinical nonequivalence. This preplanned follow-on analysis of a prospective, randomized, double-blinded, crossover study of brand and 3 generic bupropion XL 300 mg products measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations and evaluated bioequivalence and pharmacokinetics. Steady-state plasma and urine bupropion disposition was markedly stereoselective, with up to 40-fold differences in plasma concentrations of the active metabolite S,S-hydroxybupropion vs. R,R,-hydroxybupropion. Urine metabolite glucuronides were prominent, but glucuronidation was metabolite-specific and enantioselective. There were no differences between any generic and brand, or between generics, in plasma enantiomer concentrations of bupropion or the major metabolites. All generic products satisfied formal bioequivalence criteria (peak plasma concentration (Cmax ) and area under the plasma concentration-time curve over 24 hours (AUC0-24 )) using enantiomers for bupropion as well as for metabolites, and generics were comparable to each other, and were considered bioequivalent, based on enantiomeric analysis. Enantiomeric bioequivalence explains the previously observed therapeutic equivalence of bupropion generics and brand in treating major depression. These results have important implications for understanding the clinical therapeutic effects of bupropion based on complex and stereoselective metabolism.
Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Bupropiona/farmacocinética , Transtorno Depressivo Maior/tratamento farmacológico , Medicamentos Genéricos/farmacocinética , Administração Oral , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/sangue , Antidepressivos de Segunda Geração/urina , Biotransformação , Bupropiona/administração & dosagem , Bupropiona/sangue , Bupropiona/urina , Estudos Cross-Over , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Método Duplo-Cego , Medicamentos Genéricos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Eliminação Renal , Estereoisomerismo , Equivalência TerapêuticaRESUMO
Bioactivation of the antidepressant and smoking cessation drug bupropion is catalyzed predominantly by CYP2B6. The metabolite hydroxybupropion derived from t-butylhydroxylation is considered to contribute to the antidepressant and smoking-cessation effects of the parent drug. Bupropion hydroxylation is the canonical in vitro and in vivo probe for CYP2B6 activity. P450 also requires obligate partnership with P450 oxidoreductase (POR). Human CYP2B6 and POR genes are highly polymorphic. Some CYP2B6 variants affect bupropion disposition. This investigation evaluated the influence of several human CYP2B6 and POR genetic variants on stereoselective bupropion metabolism, using an insect cell coexpression system containing CYP2B6, POR, and cytochrome b 5 Based on intrinsic clearances (Clints), relative activities for S,S-hydroxybupropion formation were in the order CYP2B6.4 > CYP2B6.1 > CYP2B6.17 > CYP2B6.5 > CYP2B6.6 ≈ CYP2B6.26 ≈ CYP2B6.19 > CYP2B6.7 > CYP2B6.9 > > CYP2B6.16 and CYP2B6.18; relative activities for R,R-hydroxybupropion formation were in the order CYP2B6.17 > CYP2B6.4 > CYP2B6.1 > CYP2B6.5 ≈ CYP2B6.19 ≈ CYP2B6.26 > CYP2B6.6 > CYP2B6.7 ≈ CYP2B6.9 > > CYP2B6.16 and CYP2B6.18. Bupropion hydroxylation was not influenced by POR variants. CYP2B6-catalyzed bupropion hydroxylation is stereoselective. Though Vmax and Km varied widely among CYP2B6 variants, stereoselectivity was preserved, reflected by similar Clint(S,S-hydroxybupropion)/Clint(R,R-hydroxybupropion) ratios (1.8-2.9), except CYP2B6.17, which was less enantioselective. Established concordance between human bupropion hydroxylation in vitro and in vivo, together with these new results, suggests additional CYP2B6 variants may influence human bupropion disposition. SIGNIFICANCE STATEMENT: Bupropion pharmacokinetics, metabolism, and clinical effects are affected by the CYP2B6*6 polymorphism. Other expressed CYP2B6 polymorphisms had diminished (*5, *6, *7, *9, *19, *26) or defective (*16, *18) in vitro bupropion hydroxylation. P450 oxidoreductase genetic variants had no effect on metabolism, suggesting no clinical consequence of this polymorphism. These CYP2B6 polymorphisms may portend diminished in vivo bupropion hydroxylation and predict additional clinically important variant alleles.
Assuntos
Bupropiona/farmacocinética , Citocromo P-450 CYP2B6/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Bupropiona/química , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/isolamento & purificação , Sistema Enzimático do Citocromo P-450/genética , Ensaios Enzimáticos , Humanos , Hidroxilação , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Especificidade por SubstratoRESUMO
BACKGROUND: Cancer-related fatigue is a significant problem and is associated with poor quality of life. Behavioral interventions include exercise and cognitive-behavioral therapy, which survivors may be unwilling or unable to adopt. Pharmacologic interventions (e.g., selective serotonin reuptake inhibitors) have been disappointing. One potential therapy is the antidepressant bupropion, a norepinephrine-dopamine reuptake inhibitor that targets both inflammation and the hypothalamic-pituitary-adrenal axis. The current study is intended to provide a rigorous test of the efficacy and tolerability of bupropion for cancer-related fatigue. METHODS: A randomized, double-blind, placebo-controlled trial will examine the effects of bupropion on cancer-related fatigue. The trial will be conducted nationwide through the University of Rochester Medical Center (URMC) National Cancer Institute Community Oncology Research Program (NCORP). Disease-free breast cancer survivors (n = 422) who completed chemotherapy and/or radiotherapy 12-60 months previously and report significant fatigue will be randomized 1:1 to receive bupropion (300 mg/day) or placebo. Outcomes will be assessed at baseline and the 12-week follow-up. The primary outcome, fatigue, will be measured with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). Secondary outcomes include quality of life, depression, and drug tolerability. Exploratory outcomes include cognition and symptomatology. Potential biological mechanisms and genetic moderators of cancer-related fatigue will also be explored. DISCUSSION: This study is the first placebo-controlled trial to our knowledge to evaluate bupropion for cancer-related fatigue. Positive results could revolutionize the treatment of cancer-related fatigue, as bupropion is safe, inexpensive, widely-available, and may be more tolerable and acceptable for many patients than current, limited treatment options.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Neoplasias da Mama/complicações , Bupropiona/uso terapêutico , Sobreviventes de Câncer , Fadiga/tratamento farmacológico , Fadiga/etiologia , Fatores Etários , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/efeitos adversos , Antidepressivos de Segunda Geração/farmacocinética , Bupropiona/administração & dosagem , Bupropiona/efeitos adversos , Bupropiona/farmacocinética , Citocromo P-450 CYP2B6/genética , Preparações de Ação Retardada , Depressão/etiologia , Método Duplo-Cego , Fadiga/genética , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Menopausa , Qualidade de Vida , Projetos de Pesquisa , Fatores Socioeconômicos , Alcaloides de VincaRESUMO
BACKGROUND: Though there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase. METHODS: The mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants. RESULTS: An intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals. CONCLUSION: The outcomes of the present study revealed that particularly activation or inhibition of the CB1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.