Dose-related reduction in bupropion plasma concentrations by ritonavir.

The effect of repeat oral doses of ritonavir, at high (600 mg twice daily) and low (100 mg twice daily) doses, on the pharmacokinetics of a single dose of bupropion was evaluated in healthy volunteers. Subjects received a single dose of 150 mg of bupropion on day 1 and twice-daily ritonavir from day 8 through day 30. Ritonavir was up-titrated from 300 mg twice daily to 600 mg twice daily in the high-dose ritonavir study, whereas subjects remained on 100 mg twice-daily ritonavir in low-dose ritonavir study. Subjects received a second single dose of bupropion on day 24. Serial blood samples were obtained to evaluate the pharmacokinetics of bupropion and its metabolites on days 1 and 24. Steady-state ritonavir led to a decrease of area under the curve and maximum plasma concentration of bupropion by 62% to 67% in the high-dose study and by 21% to 22% in the low-dose study, indicating a drug interaction of statistical and clinical significance, particularly at high doses of ritonavir. These studies demonstrate that the reduction of bupropion exposure by ritonavir is dose-related. Dosage adjustment of bupropion may be needed when administered with ritonavir. However, the maximum recommended daily dose of bupropion should not be exceeded.

An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction.

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 bupropion's 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 (K(i) = 1.7 and 5.4 microM, respectively) than hydroxybupropion (K(i) = 13 microM) or bupropion (K(i) = 21 microM). 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 for major depressive disorder: Pharmacokinetic and formulation considerations.

BACKGROUND: Major depressive disorder (MDD) is a common psychiatric condition, with 6.6% of the adult population in the United States experiencing a major depressive episode during any given year. Depressed patients must receive adequate treatment to maximize the likelihood of clinical success. Bupropion hydrochloride, a noradrenergic/dopaminergic antidepressant, is available in 3 oral formulations: immediate release (IR) (given TID), sustained release (SR) (given BID), and extended release (XL) (given QD). Understanding the pharmacokinetic (PK) properties and formulations of bupropion can help optimize clinical use. OBJECTIVES: : The aims of this article were to provide a review of the PK properties of bupropion and identify its various formulations and clinical applications to help optimize treatment of MDD. METHODS: : In this review, data concerning PK trials/reports were collected from articles identified using a PubMed search. The search was conducted without date limitations and using the search terms bupropion, bupropion SR, bupropion XL, bupropion pharmacokinetics, bupropion metabolism, and bupropion drug interactions. Additional reports were selected from references that appeared in articles identified in the original search. In addition, data from studies summarized in product information and labeling were obtained. All available information, concentrating on studies in humans, pertinent to bupropion PK properties and/or formulations was included. RESULTS: : Bupropion is extensively metabolized by the liver (t(1/2), approximately 21 hours). Hydroxybupropion, the primary active metabolite (t(1/2), approximately 20 hours), is formed by cytochrome P450 (CYP) 2B6. At steady state, C(max) of hydroxybupropion is 4- to 7-fold higher, and the AUC is approximately 10-fold greater, compared with those of the parent drug. Threohydrobupropion and erythrohydrobupropion (mean [SD] t(1/2) values, approximately 37 [13] and approximately 33 [10] hours, respectively), the other active metabolites of bupropion, are formed via nonmicrosomal pathways. Relative to bupropion, the C(max) values are approximately 5-fold greater for threohydrobupropion and similar for erythrohydrobupropion. Based on a mouse antitetrabenazine model, hydroxybupropion is approximately 50% as active as bupropion, and threohydrobupropion and erythrohydrobupropion are approximately 20% as active as bupropion. Bupropion lowers the seizure threshold and, therefore, concurrent administration with other agents that lower the seizure threshold should be undertaken cautiously. Potential interactions with other agents that are metabolized by CYP2B6 should be considered. In addition, bupropion inhibits CYP2D6 and may reduce clearance of agents metabolized by this enzyme. Absorption of the XL formulation is prolonged compared with the IR and SR formulations (T(max), approximately 5 hours vs approximately 1.5 and approximately 3 hours, respectively). Bupropion is dosed without regard to food. CONCLUSIONS: : Understanding the PK profile and formulations of bupropion can help optimize clinical use. Bupropion is metabolized extensively, resulting in 3 active metabolites. This metabolic profile, various patient factors (eg, age, medical illnesses), and potential drug interactions should be considered when prescribing bupropion. The 3 formulations-bupropion, bupropion SR, and bupropion XL-are bioequivalent and offer options to optimize treatment for patients with MDD.

In vitro remifentanil metabolism: the effects of whole blood constituents and plasma butyrylcholinesterase.

UNLABELLED: We designed this in vitro study to determine whether the half-life of remifentanil was altered in butyrylcholinesterase-deficient patients. Test tubes containing Krebs buffered solution, whole blood, plasma, or red cells from both normal and butyrylcholinesterase-deficient patients were incubated with remifentanil. Remifentanil concentrations were determined by using gas chromatography and mean half-lives were calculated by using a nonlinear regression analysis. There were no differences in whole blood, red cells, or plasma half-life between normal and butyrylcholinesterase-deficient volunteers. In both normal and butyrylcholinesterase-deficient volunteers, whole blood and plasma had a significantly longer half-life than the red cell component. Extrapolation to the in vivo setting would suggest that a butyrylcholinesterase-deficient patient should not have altered remifentanil kinetics. IMPLICATIONS: This was a test-tube-designed study to determine whether an enzyme deficiency (butyrylcholinesterase deficiency) changes the way remifentanil is metabolized. It seems that remifentanil dosage does not need to be changed in patients with butyrylcholinesterase deficiency.