Potentiation of Antidepressant Effects of Agomelatine and Bupropion by Hesperidin in Mice
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Hesperidin, a well-known flavanone glycoside mostly found in citrus fruits, showed neuroprotective and antidepressant activity. Agomelatine, a melatonergic MT 1 /MKeywords:
Bupropion
Agomelatine
Bupropion
Sertraline
CYP2B6
Active metabolite
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Woohwangcheongsimwon suspension has traditionally been used for the treatment and prevention of stroke, hypertension, palpitations, convulsions and unconsciousness in various Asian countries. Woohwangcheongsimwon suspensions showed an inhibitory effect on CYP2B6 activity in vitro. Two terpenoids, borneol and isoborneol, are major constituents of woohwangcheongsimwon suspension, and show a competitive inhibition of CYP2B6 with K(i) values of 9.5 and 5.9 microM, respectively. Bupropion undergoes metabolic transformation to the active metabolite, 4-hydroxybupropion, primarily via CYP2B6 both in vivo and in vitro. It is often used as a CYP2B6 substrate for clinical drug-drug interaction studies. Drug interactions may occur between woohwangcheongsimwon suspension and bupropion.Co-administration with woohwangcheongsimwon suspension did not alter the pharmacokinetics of bupropion or its metabolite, 4-hydroxybupropion. Dosage adjustment of bupropion is unnecessary in patients concomitantly administered the highest recommended daily dose of woohwangcheongsimwon suspension.To examine the effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, formed via CYP2B6 in vivo.A two-way crossover clinical trial with a 2 week washout period was conducted in 14 healthy volunteers. In phases I and II, subjects received 150 mg bupropion with or without woohwangcheongsimwon suspension four times (at -0.17, 3.5, 23.5 and 47.5 h, with the time of bupropion administration taken as 0 h) in a randomized balanced crossover order. Bupropion and 4-hydroxybupropion plasma concentrations were measured for up to 72 h by LC-MS/MS. Urine was collected up to 24 h to calculate the renal clearance. In addition, the CYP2B6*6 genotype was also analyzed.The geometric mean ratios and 90% confidence interval of bupropion with woohwangcheongsimwon suspension relative to bupropion alone were 0.976 (0.917, 1.04) for AUC(0,infinity) and 0.948 (0.830,1.08) for C(max), respectively. The corresponding values for 4-hydroxybupropion were 0.856 (0.802, 0.912) and 0.845 (0.782, 0.914), respectively. The t(max) values of bupropion and 4-hydroxybupropion were not significantly different between the two groups (P > 0.05). The pharmacokinetic parameters of bupropion and 4-hydroxybupropion were unaffected by woohwangcheongsimwon suspension.These results indicate that woohwangcheongsimwon suspension has a negligible effect on the disposition of a single dose of bupropion in vivo. As a result, temporary co-administration with woohwangcheongsimwon suspension does not seem to require a dosage adjustment of bupropion.
Bupropion
Active metabolite
Crossover study
CYP2B6
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A drug-drug interaction study was conducted to determine whether ritonavir (200 mg; 4 doses over 2 days) alters the pharmacokinetic disposition of bupropion (75 mg; once) coadministered to 7 healthy volunteers in a placebo-controlled 2-way crossover study. Serum samples collected from 0 to 24 hours after bupropion administration were assayed for concentrations of bupropion and metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Derived pharmacokinetic parameters were compared between placebo/bupropion and ritonavir/bupropion trials by paired t test. The effect of ritonavir on most pharmacokinetic parameters was minimal (<20% mean change). The only parameters that showed a statistically significant effect were threohydrobupropion area under the blood concentration curve (14% +/- 5% decrease, mean +/- SE; P = .04) and erythrohydrobupropion time-to-maximal serum concentration (161% +/- 92% increase, P = .03), suggesting that ritonavir may inhibit the carbonyl reductase enzyme responsible for formation of these metabolites. These findings indicate that short-term ritonavir dosing has only minimal impact on the pharmacokinetic disposition of a single dose of bupropion in healthy volunteers.
Bupropion
Ritonavir
Crossover study
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Bupropion is an atypical antidepressant that is biotransformed in humans to its major active metabolite hydroxybupropion by cytochrome P450 2B6 (CYP2B6). Co-administration of bupropion with an inhibitor of CYP2B6 can result in a serious drug interaction, leading to bupropion related adverse effects (e.g. seizures). The antiplatelet agent ticlopidine has been identified as a potent in vitro inhibitor of bupropion hydroxylation, however it is unknown if it interacts in vivo in rodents. In this study we investigated the potential pharmacokinetic (PK) drug interaction between bupropion and ticlopidine in mice. Using a destructive sampling design, male CF-1 mice were administered ticlopidine 1.0 mg/kg daily for 5 d, followed by single-dose bupropion 50 mg/kg. Bupropion and hydroxybupropion levels were measured by HPLC-UV in plasma and brain tissues at 30, 60, 90, 120 and 180 min post-dose, and compared between treatment groups. There was a strong trend in both plasma and brain data towards greater bupropion levels and smaller hydroxybupropion levels in ticlopidine treated mice. Analysis of variance indicated statistical differences (p<0.05) at many time points. The variance associated with the area under the curve was calculated using Bailer's method and significant differences were found between treatment groups. Taken together, the concentration time point statistical analysis followed by PK modeling demonstrate a significant PK drug interaction between bupropion and ticlopidine. To our knowledge, this is the first study to document an in vivo drug interaction between these drugs in mice. Our findings support future in vivo drug interaction studies in mice between bupropion and CYP2B6 inhibitors.
Bupropion
Ticlopidine
CYP2B6
Tacrine
Active metabolite
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Bupropion is a popular antidepressant that is also prescribed in the management of smoking cessation. In humans, bupropion is predominantly metabolized to its active metabolite hydroxybupropion by CYP2B6. Inhibitors of CYP2B6 have the potential to decrease the clearance of bupropion, leading to adverse drug toxicity. We sought to develop a sensitive HPLC‐UV assay to quantify plasma and brain concentrations of bupropion and hydroxybupropion; and apply the assay to assess in vivo pharmacokinetic (PK) drug‐drug interaction (DDI) studies between bupropion and potent CYP2B6 inhibitors. Tissue extraction followed by HPLC‐UV detected timolol (IS), hydroxybupropion and bupropion at 6, 11 and 36 minutes, respectively. The LOD for both compounds was 6.0 ng/ml, and the intra‐day and inter‐day coefficients of variation was ±12% in plasma and ±15% in whole brain tissue. We then utilized this novel technique to evaluate the PK of bupropion and hydroxybupropion following repeated administration of the known CYP2B6 inhibitor ticlopidine (5 mg/kg daily x 5 days) in CF‐1 mice. Ticlopidine increased the plasma area under the concentration curve ( AUC) of bupropion (2.0‐fold, p< 0.01) and decreased the plasma AUC of hydroxybupropion (1.2‐fold;p< 0.05). In whole brain tissue, ticlopidine increased the AUC of bupropion (1.3‐fold;p> 0.05)and decreased the AUC of hydroxybupropion (2.0‐fold;p< 0.001). In summary, we have developed a sensitive HPLC assay and suitable rodent model to evaluate in vivo PK DDI between bupropion and CYP2B6 inhibitors. Support: Drake Univ COPHS Intramural Research Grants.
Bupropion
CYP2B6
Active metabolite
Tacrine
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Bupropion
Reuptake
Active metabolite
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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite hydroxybupropion almost exclusively by CYP2B6. • Ginkgo biloba is among the most commonly used herbal extract in the general population, and is likely to be used by depressed patients receiving bupropion. • Studies have reported that G. biloba administration to rats markedly increased the CYP content and CYP2B mRNA in the liver, and intake of G. biloba also induced various hepatic CYP enzymes, especially CYP2B‐type enzymes. • There may be drug interactions between G. biloba extract and bupropion (CYP2B6 substrate). WHAT THIS STUDY ADDS • Fourteen‐day oral administration of G. biloba extract had no statistically significant effect on the pharmacokinetics of bupropion or its active metabolite hydroxybupropion, as measured by AUC, which suggests G. biloba does not significantly affect the metabolism of bupropion following a single oral dose in healthy Chinese men. AIMS To assess the effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. METHODS Fourteen healthy male volunteers (age range 19–25 years) received orally administered bupropion (150 mg) alone and during treatment with G. biloba 240 mg day −1 (two 60‐mg capsules taken twice daily) for 14 days. Serial blood samples were obtained over 72 h after each bupropion dose, and used to derive pharmacokinetic parameters of bupropion and its CYP2B6‐catalysed metabolite, hydroxybupropion. RESULTS Ginkgo biloba extract administration resulted in no significant effects on the AUC 0–∞ of bupropion and hydroxybupropion. Bupropion mean AUC 0–∞ value was 1.4 µg·h ml −1 [95% confidence interval (CI) 1.2, 1.6] prior to G. biloba treatment and 1.2 µg·h ml −1 (95% CI 1.1, 1.4) after 14 days of treatment. Hydroxybupropion mean AUC 0–∞ value was 8.2 µg·h ml −1 (95% CI 6.5, 10.4) before G. biloba administration and 8.7 µg·h ml −1 (95% CI 7.1, 10.6) after treatment. The C max of hydroxybupropion increased from 221.8 ng ml −1 (95% CI 176.6, 278.6) to 272.7 ng ml −1 (95% CI 215.0, 345.8) ( P = 0.038) and the t 1/2 of hydroxybupropion fell from 25.0 h (95% CI 22.7, 27.5) to 21.9 h (95% CI 19.9, 24.1) ( P = 0.000). CONCLUSIONS Ginkgo biloba extract administration for 14 days does not significantly alter the basic pharmacokinetic parameters of bupropion in healthy volunteers. Although G. biloba extract treatment appears to reduce significantly the t 1/2 and increase the C max of hydroxybupropion, no bupropion dose adjustments appear warranted when the drug is administered orally with G. biloba extract, due to the lack of significant change observed in AUC for either bupropion or hydroxybupropion.
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Active metabolite
CYP2B6
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There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolized drug desipramine resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in bupropion clearance, and bupropion and its major active metabolite, hydroxybupropion, are not strong CYP2D6 inhibitors in vitro. The aims of this study were to investigate whether bupropion9s reductive metabolites, threohydrobupropion and erythrohydrobupropion, contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, erythrohydrobupropion and threohydrobupropion were more potent inhibitors of CYP2D6 activity (Ki = 1.7 and 5.4 μM, respectively) than hydroxybupropion (Ki = 13 μM) or bupropion (Ki = 21 μM). Furthermore, neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors. Using the in vitro kinetic constants and estimated liver concentrations of bupropion and its metabolites, modeling was able to predict within 2-fold the increase in desipramine exposure observed when coadministered with bupropion. This work indicates that the reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo and provides a mechanistic explanation for the clinical drug-drug interaction between bupropion and desipramine.
Bupropion
Desipramine
Active metabolite
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The data obtained in these studies show that the antidepressant activity of bupropion cannot be explained by its ability to inhibit MAO present in brain or to increase the release of biogenic amines from nerve endings, since the drug possesses neither of these properties. It is also unlikely that the weak properties of the drug as an inhibitor of dopamine uptake in brain can explain its antidepressant activity. It is clear, however, that dopamine neurons must be present for the CNS properties of bupropion to be manifested in animal models; at antidepressant doses of the drug, dopamine turnover is reduced in brain. Finally, the antidepressant properties of bupropion have been dissociated from down-regulation of postsynaptic beta-receptors. To our knowledge, bupropion is the first clinically effective antidepressant whose mechanism of action cannot be explained on the basis of alterations in either presynaptic events or postsynaptic receptor-mediated events in catecholamine or serotonin pathways. Thus, bupropion is a novel antidepressant whose mechanism of action must still be elucidated.
Bupropion
Mechanism of Action
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The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites-hydroxybupropion, threohydrobupropion and erythrohydrobupropion-based on a mixed "bottom-up" and "top-down" approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (Cmax) area under the concentration-time curve (AUC) values and Cmax and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and Cmax ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory metabolites.
Bupropion
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