Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation

AIM: Our objective was to study the effect of hormone replacement therapy and a combination oral contraceptive on the cytochrome P450 (CYP) 2B6 activity with bupropion (INN, amfebutamone) hydroxylation used as a probe reaction. METHODS: This was a 3-way crossover study with 12 healthy female volunteers. The first phase was a control phase, in which all subjects received a single 150-mg dose of bupropion (sustained release) without pretreatment. In the second and third phases, in randomized balanced crossover order, subjects received a 10-day pretreatment with either hormone replacement therapy, containing 2 mg estradiol valerate and 250 microg levonorgestrel, or an oral contraceptive, containing 30 microg ethinyl estradiol (INN, ethinylestradiol) and 150 microg desogestrel, and the bupropion dose was given 1 hour after the last hormone dose. The bupropion, hydroxybupropion, and hydrobupropion plasma concentrations were determined for up to 72 hours. RESULTS: The 10-day hormone replacement therapy pretreatment reduced the hydroxybupropion/bupropion area under the plasma concentration-time curve (AUC) ratio by 49% (P <.001; 95% confidence interval [CI], -58% to -40%) as a result of a marked 47% decrease (P <.001; 95% CI, -54% to -41%) in the AUC of hydroxybupropion. Moreover, the AUC of hydrobupropion was significantly (64%; P =.003; 95% CI, 22% to 106%) increased. The AUC of hydroxybupropion was also reduced after the oral contraceptive treatment but to a lesser extent (-31%; P <.001; 95% CI, -37% to -26%). However, the hydroxybupropion/bupropion AUC ratio was not significantly affected. CONCLUSIONS: Hormone replacement therapy markedly inhibited the CYP2B6-catalyzed hydroxylation of bupropion, whereas a combination oral contraceptive had only a modest effect on CYP2B6 activity. Patients receiving hormone replacement therapy or oral contraceptives may need dose adjustment when treated with drugs metabolized by CYP2B6.     

Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation

OBJECTIVE: Our objective was to study the effect of the antiplatelet agents clopidogrel and ticlopidine on bupropion (INN, amfebutamone) hydroxylation, a probe reaction for cytochrome P450 (CYP) 2B6 activity. METHODS: Twelve healthy male volunteers took a single 150-mg oral dose of bupropion either alone or after pretreatment with 75 mg clopidogrel once daily or 250 mg ticlopidine twice daily for 4 days. On day 4, a single 150-mg oral dose of bupropion was administered. Plasma concentrations of bupropion and its CYP2B6-catalyzed metabolite, hydroxybupropion, were measured for up to 72 hours. RESULTS: The mean area under the plasma concentration-time curve (AUC) of hydroxybupropion calculated from time 0 to infinity was reduced by 52% ( P = .001; 95% confidence interval [CI], 39% to 66%) by clopidogrel and by 84% ( P < .0001; 95% CI, 73% to 94%) by ticlopidine. Clopidogrel reduced the AUC ratio of hydroxybupropion over bupropion by 68% ( P = .002; 95% CI, 58% to 77%) and ticlopidine by 90% ( P = .001; 95% CI, 85% to 96%). The AUC of bupropion was increased by 60% ( P = .02; 95% CI, 21% to 98%) and by 85% ( P < .0001; 95% CI, 48% to 85%) with clopidogrel and ticlopidine, respectively. CONCLUSIONS: Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalyzed bupropion hydroxylation. Patients receiving either clopidogrel or ticlopidine are likely to require dose adjustments when treated with drugs primarily metabolized by CYP2B6.     

Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects

BACKGROUND AND OBJECTIVE: Rifampin (INN, rifampicin) causes several drug interactions with coadministered antidiabetic drugs. Rosiglitazone is a novel thiazolidinedione antidiabetic drug, but little is known about the drug interaction between rifampin and rosiglitazone. Our objective was to investigate the effect of rifampin on the pharmacokinetics of rosiglitazone in humans. METHOD: In an open-label, randomized, 2-way crossover study, 10 healthy Korean male subjects were treated once daily for 6 days with 600 mg rifampin or with placebo. On day 7, a single dose of 8 mg rosiglitazone was administered orally. Plasma rosiglitazone concentrations were measured. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve for rosiglitazone by 65% (2947.9 ng. h/mL versus 991.5 ng. h/mL, P <.001) and the mean elimination half-life from 3.9 to 1.5 hours (P <.001). The peak plasma concentration of rosiglitazone was significantly decreased by rifampin (537.7 ng/mL versus 362.3 ng/mL, P <.01). The apparent oral clearance of rosiglitazone increased about 3-fold after rifampin treatment (2.8 L/h versus 8.5 L/h, P <.001). CONCLUSION: This study showed that rifampin affected the disposition of rosiglitazone in humans, probably by the induction of cytochrome P450 (CYP) 2C8 and, to a lesser extent, CYP2C9. Therefore caution should be exercised during the coadministration of rifampin and rosiglitazone.     

The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron

BACKGROUND: Ondansetron is an antiemetic agent metabolized by cytochrome P450 (CYP) enzymes. Rifampin (INN, rifampicin) is a potent inducer of CYP3A4 and some other CYP enzymes. We examined the possible effect of rifampin on the pharmacokinetics of orally and intravenously administered ondansetron. METHODS: In a randomized crossover study with 4 phases and a washout of 4 weeks, 10 healthy volunteers took either 600 mg rifampin (in 2 phases) or placebo (in 2 phases) once a day for 5 days. On day 6, 8 mg ondansetron was administered either orally (after rifampin and placebo) or intravenously (after rifampin and placebo). Ondansetron concentrations in plasma were measured up to 12 hours. RESULTS: The mean total area under the plasma concentration-time curve [AUC(0-infinity)] of orally administered ondansetron after rifampin pretreatment was reduced by 65% compared with placebo (P < .001). Rifampin decreased the peak plasma concentration of oral ondansetron by about 50% (from 27.2+/-3.0 to 13.8+/-1.5 ng/mL [mean +/- SEM]; P < .001]) and the elimination half-life (t1/2) by 38% (P < .01). The bioavailability of oral ondansetron was reduced from 60% to 40% (P < .01) by rifampin. The clearance of intravenous ondansetron was increased 83% (from 440+/-38.4 to 805+/-44.6 mL/min [P < .001]) by rifampin. Rifampin reduced the t1/2 of intravenously administered ondansetron by 46% (P < .001) and the AUC(0-infinity) by 48% (P < .001). CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of ondansetron after both oral and intravenous administration. The interaction is most likely the result of induction of the CYP3A4-mediated metabolism of ondansetron. Concomitant use of rifampin or other potent inducers of CYP3A4 with ondansetron may result in a reduced antiemetic effect, particularly after oral administration of ondansetron.     

CYP3A5 genotype has a dose-dependent effect on ABT-773 plasma levels

BACKGROUND: The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial. OBJECTIVE: Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein) influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate for both CYP3A and P-glycoprotein. METHODS: Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area under the plasma concentration-time curves (AUCs) from 0 to 6 hours (AUC(t)) and maximum postdose plasma concentration (C(max)) after a single dose and on day 5 of a twice-daily regimen were calculated and correlated with genotypes. RESULTS: ABT-773 AUC(t) and C(max) were, on average, higher in CYP3A5-negative subjects given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical doses (n = 8). The relationship for AUC(t) was statistically significant both after a single dose (geometric mean and 95% confidence interval [CI], 5.0 microg.h/mL [3.9-6.4 microg.h/mL] versus 2.8 microg.h/mL [1.8-4.3 microg.h/mL]; P =.03) and on the fifth day of twice-daily dosing (12.4 microg.h/mL [8.7-17.6 microg.h/mL] versus 7.4 microg.h/mL [5.5-9.8 microg.h/mL], P =.04). The relationship for C(max) was statistically significant after a single dose (1220 microg/mL [867-1167 microg/mL] versus 727 microg/mL [506-1044 microg/mL], P =.04) and showed a trend in the same direction on the fifth day of twice-daily dosing (2566 microg/mL [1813-3631 microg/mL] versus 1621 microg/mL [1122-2343 microg/mL], P =.07). In contrast, AUC(t) and C(max) were not significantly different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or 300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes. CONCLUSIONS: These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose-dependent.     

Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of antipsychotic risperidone in healthy volunteers

BACKGROUND: Although cytochrome P450 (CYP) 2D6 is often thought to be the only CYP responsible for the metabolism of risperidone, many reports suggest that CYP3A may be involved too. Rifampin, a potent CYP3A inducer, has been known to markedly decrease plasma concentrations of various drugs, which are concomitantly administered during treatment. OBJECTIVE: To examine the effect of rifampin on plasma concentrations of a single oral dose of risperidone in healthy Thai male volunteers. METHODS: In an open, randomized two-phase crossover study, separated by a 2-week period, 10 healthy Thai male volunteers received a single oral dose of 4-mg risperidone alone or with 600 mg rifampin, orally once daily for 5 days. Serial blood samples were collected at specific time points for a 48-h period. Risperidone was measured in plasma using high performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined by using non-compartmental analysis. RESULTS: Co-administration with 600-mg rifampin once daily for 5 days was associated with a significant decrease in risperidone area under the curve (AUC(0-48)) and maximal concentration (C(max)) by 72% (157 x 49 +/- 48 x 80 vs. 42 x 66 +/- 7 x 81 ng/L/h; P<0 x 01) and 50% (32 x 44 +/- 6 x 05 vs. 16 x 16 +/- 2 x 73 ng/mL; P<0 x 05), respectively when compared with risperidone alone. CONCLUSIONS: Rifampin when used concurrently with risperidone significantly decreases the plasma concentration of risperidone. Our results provide in vivo evidence of the involvement of CYP3A in the metabolism of risperidone, in addition to CYP2D6. Thus, co-administration of risperidone with CYP3A inducer(s), including rifampin should be recognized or avoided in clinical practice.     

Effect of Rifampin on the Pharmacokinetics of Ertugliflozin in Healthy Subjects

Purpose

Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin.

Rifampin decreases the plasma concentrations and effects of repaglinide

OBJECTIVE: To study the effects of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of repaglinide, a new short-acting antidiabetic drug. METHODS: In a randomized, two-phase crossover study, nine healthy volunteers were given a 5-day pretreatment with 600 mg rifampin or matched placebo once daily. On day 6 a single 0.5-mg dose of repaglinide was administered. Plasma repaglinide and blood glucose concentrations were measured up to 7 hours. RESULTS: Rifampin decreased the total area under the concentration-time curve of repaglinide by 57% (P < .001) and the peak plasma repaglinide concentration by 41% (P = .001). The elimination half-life of repaglinide was shortened from 1.5 to 1.1 hours (P < .01). The blood glucose decremental area under the concentration-time curve from 0 to 3 hours was reduced from 0.94 to -0.23 mmol/L x h (P < .05), and the maximum decrease in blood glucose concentration from 1.6 to 1.0 mmol/L (P < .05) by rifampin. CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of repaglinide and also reduces its effects. This interaction is probably caused by induction of the CYP3A4-mediated metabolism of repaglinide. It is probable that the effects of repaglinide are decreased during treatment with rifampin or other potent inducers of CYP3A4, such as carbamazepine, phenytoin, or St John's wort.     

Interactions of colistin and rifampin on multidrug-resistant Acinetobacter baumannii

The increased incidence of nosocomial infections by multidrug-resistant Acinetobacter spp creates demand on the application of some combinations of older antimicrobials on that species. The in vitro activities of colistin and of rifampin and of their interaction were tested on 39 nosocomial isolates of Acinetobacter baumannii. All isolates were resistant to ampicillin/sulbactam, to 3(rd) and 4(th) generation cephalosporins, to amikacin and to ciprofloxacin. MICs were determined by a microdilution technique and interactive studies between 1x or 4x MIC of colistin and rifampin were performed by the time-kill assay. Rifampin was applied at a concentration of 2 microg/mL which is equal to its mean serum level. All isolates were inhibited by colistin and only 15.2% by rifampin. Synergy between 1x MIC of colistin and rifampin was detected in 15.4% of isolates at 6 h of growth and in 51.3% of isolates at 24 h of growth. Synergy between 4x MIC of colistin and rifampin was detected in 15.4% of isolates at 6 h of growth and in 66.7% of isolates at 24 h of growth. It is concluded that colistin is highly active on multidrug-resistant Acinetobacter spp and its activity on A.baumannii is increased in the presence of rifampin, so that their administration might be proposed for nosocomial infections by these isolates.     

Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor metabolizers.

Lansoprazole is a potent gastric proton pump inhibitor that is metabolized by CYP2C19 but appears to induce the activity of hepatic microsomal CYP1A2 in a concentration-dependent manner. Because the inducing effect appears to be a dose-dependent phenomenon, it may be more important in poor metabolizers of CYP2C19 who have more than four times the area under the lansoprazole plasma concentration-time curve (AUC) and constitute 12% to 23% of Asian populations. Theophylline owes a significant portion of its metabolism to CYP1A2 and can cause gastric acid reflux that calls for concurrent use of proton pump inhibitors. We conducted a prospective, randomized, subject-blind, multicenter crossover study of the effect of multiple high-dose oral lansoprazole (30 mg twice a day for 7 days) on the pharmacokinetics of a single intravenous dose of theophylline (4.73 mg/kg) in healthy volunteers characterized for CYP2C19 genotype. The study compared the pharmacokinetics of lansoprazole and theophylline in five white extensive metabolizers, six Korean extensive metabolizers, and seven poor metabolizers of CYP2C19. The pharmacokinetics of lansoprazole were significantly different among groups; AUC values were 1.55+/-0.20 microg x h/mL in white extensive metabolizers, 7.01+/-0.72 microg x hr/mL in Korean extensive metabolizers, and 14.34+/-2.60 microg x h/mL in poor metabolizers (P < .001). The administration of lansoprazole did not change intravenous theophylline clearance compared with placebo in any group, and theophylline clearance exhibited no correlation with AUC of lansoprazole (rs = 0.12; P > .1). These data suggest that usual therapeutic doses of lansoprazole have no clinically significant influence on the clearance of theophylline, even in poor metabolizers of CYP2C19.     

Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype

OBJECTIVES: Rosiglitazone is metabolically inactivated predominantly via the cytochrome P450 (CYP) enzyme CYP2C8. The functional impact of the CYP2C8*3 allele coding for the Arg139Lys and Lys399Arg amino acid substitutions is controversial. The purpose of this was to clarify the role of this polymorphism with regard to the pharmacokinetics and clinical effects of rosiglitazone. METHODS: From a large sample of healthy volunteers, 14 carriers of the CYP2C8*1/*1 allele, 13 carriers of the *1/*3 allele, and 4 carriers the *3/*3 allele were selected for a clinical study. Rosiglitazone (8 mg) single-dose and multiple-dose pharmacokinetics and its effects on glucose level and body weight were monitored. Plasma and urine concentrations of rosiglitazone and desmethylrosiglitazone were measured, and kinetics was analyzed by noncompartmental and population-kinetic compartmental methods. RESULTS: Mean total clearance values were 0.033 L x h(-1) x kg(-1) (95% confidence interval [CI], 0.030-0.037 L x h(-1) x kg(-1)), 0.038 L x h(-1) x kg(-1) (95% CI, 0.033-0.044 L x h(-1) x kg(-1)), and 0.046 L x h(-1) x kg(-1) (95% CI, 0.033-0.058 L x h(-1) x kg(-1)) in carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, on day 1 (P = .02, ANOVA [F test]). Rosiglitazone kinetics could be adequately described by a 1-compartmental model with first-order absorption. Besides CYP2C8 genotype, body weight was a significant covariate (P < .001, log-likelihood ratio test). Elimination half-lives were 4.3, 3.5, and 2.9 hours in CYP2C8*1/*1, *1/*3, and *3/*3 carriers, respectively. Clearance of desmethylrosiglitazone was also higher in CYP2C8*3 allele carriers, with mean values of 1.96 L/h (95% CI, 1.42-2.69 L/h), 2.22 L/h (95% CI, 1.61-3.04 L/h), and 2.47 L/h (95% CI, 1.80-3.39 L/h), respectively (P = .03). The plasma glucose area under the concentration curve was significantly lower after 14 days of taking rosiglitazone compared with day 1 (P = .01, paired t test), but no relationship of the glucose-lowering effect of rosiglitazone with CYP2C8 genotype was observed. CONCLUSIONS: This study showed that the CYP2C8*3 allele confers higher in vivo metabolic capacity than the wild-type CYP2C8*1 allele but the pharmacokinetic differences resulting from CYP2C8*3 were quantitatively moderate.     

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive

BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.     

CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects

BACKGROUND: Although cytochrome P450 (CYP) 2C9 was thought to be the main pathway for glyburide (INN, glibenclamide) metabolism in vivo, studies in vitro indicated that CYP2C19 had a more dominant effect. This study investigated the relative influence of CYP2C9 and CYP2C19 genotypes on the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects. METHODS: Three groups of healthy male Chinese subjects (n=6 per group) were enrolled, as follows: group I, CYP2C9*1/*1 and CYP2C19 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2C19 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. Subjects received single oral doses of 5 mg glyburide. Multiple blood samples were collected, and the plasma glyburide concentrations were determined by an HPLC method. The plasma glucose and insulin concentrations were also measured up to 2 hours after dosing. RESULTS: No significant differences in glyburide pharmacokinetics were observed between CYP2C19 EM and PM subjects who had the CYP2C9*1/*1 genotype (group I versus group II). Their respective values for area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity) and elimination half-life (t1/2) were 0.46+/-0.13 microg.h/mL versus 0.57+/- 0.11 microg.h/mL (P=.569) and 2.09+/-0.22 hours versus 2.24+/- 0.27 hours (P=.721). However, significant increases in AUC(0-infinity) (125% and 82%; P=.008 and .024, respectively) and t1/2 (71% and 60%; P=.003 and .007, respectively) were observed when CYP2C9*1/*3 subjects (group III) were compared with CYP2C9*1/*1 subjects in group I or II. Blood glucose reductions at 2 hours after dosing were 41.8%, 23.9%, and 27.7% in groups I, II, and III, respectively (P=.029), and hypoglycemia developed in 3 of 6 CYP2C9*1/*3 carriers and 2 of 12 CYP2C9*1/*1 carriers. CONCLUSION: CYP2C9, but not CYP2C19, polymorphism appears to exert a dominant influence on glyburide pharmacokinetics and pharmacodynamics in vivo. Further studies in diabetic patients with long-term dosing are warranted to confirm these findings.     

Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects

This study was conducted to investigate the effect of rifampin on the pharmacokinetics of bosentan. Healthy male subjects received bosentan 125 mg b.i.d. for 6.5 days in the presence or absence of rifampin 600 mg once a day. In vitro experiments were performed to investigate the effect of rifampin on the uptake of bosentan into Chinese hamster ovary cells expressing the human organic anion-transporting polypeptide (OATP)1B1, -1B3, and -2B1. Following the first concomitant administration, there was a fivefold increase in bosentan trough concentrations. At steady state, concomitant rifampin significantly decreased exposure to bosentan by 58%. Rifampin potently inhibited the uptake of bosentan into cells expressing human OATP1B1 and -1B3. Rifampin decreased the exposure to bosentan consistent with its known cytochrome P450 enzyme-inductive properties. The initial increase in bosentan concentrations can be explained by an inhibitory effect of rifampin on hepatic drug transporters.     

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.     

Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers

BACKGROUND AND OBJECTIVE: Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent enzyme inducer of CYP-mediated metabolism (especially CYP2C9, CYP2C19, and CYP3A4), is known to markedly decrease plasma concentrations and effects of a number coadministered drugs. The aim of this investigation was to study the possible pharmacokinetic interaction between rifampin and praziquantel. METHODS: An open, randomized, 2-phase crossover design was used in each study of single or multiple doses. In the single-dose study, 10 healthy Thai male volunteers ingested single doses of 40 mg/kg praziquantel alone (phase 1) or after pretreatment with 600 mg of oral rifampin once daily for 5 days (phase 2). In the multiple-dose study, all participants received multiple doses of 25 mg/kg praziquantel alone (phase 1) or after 5-day pretreatment with 600 mg of oral rifampin once daily (phase 2). Plasma concentrations of praziquantel in each phase were determined by the HPLC method. RESULTS: In the single-dose study, rifampin decreased plasma praziquantel concentrations to undetectable levels in 7 of 10 subjects, whereas praziquantel concentrations were reduced by rifampin to undetectable levels in 5 of 10 subjects in the multiple-dose study. In 3 subjects with measurable concentrations in the single-dose study, rifampin significantly decreased the mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of praziquantel by 81% (P <.05) and 85% (P <.01), respectively, whereas rifampin significantly decreased the mean C(max) and AUC(0-24) of praziquantel by 74% (P <.05) and 80% (P <.01), respectively, in 5 subjects with measurable concentrations in the multiple-dose study. The mean C(max) and AUC(0-24) of praziquantel in subjects whose praziquantel concentrations could not be detected in the single-dose study (7 subjects) after rifampin pretreatment were reduced by approximately 99% (P <.001) and 94% (P <.001), respectively, and in the multiple-dose study (5 subjects), they were reduced by 98% (P <.05) and 89% (P <.01), respectively. CONCLUSIONS: Rifampin greatly decreased plasma concentrations of single and multiple oral doses of praziquantel to levels lower than that of the minimum therapeutic concentration. Because praziquantel and rifampin are widely used in the treatment of liver flukes (Opisthorchis viverrini) and Mycobacterium tuberculosis, respectively, in Thailand and in some other countries in southeast Asia, the possibility of one drug influencing the pharmacokinetics of the other must be considered. Therefore simultaneous use of rifampin and praziquantel must be avoided in medical practice to optimize the therapeutic efficacy of praziquantel.     

Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion

Abstract

Context. Bupropion overdose commonly causes generalized seizures and central nervous system depression. Less commonly, cardiotoxicity has been reported. The toxicity of the parent drug compared to its active metabolite hydroxybupropion is uncertain. Case details. A 31-year-old man presented to the emergency department with altered mental status after an intentional overdose of bupropion. Three hours after admission he developed status epilepticus requiring intubation, and 13 h after admission he developed marked widening of the QRS complex and prolongation of the QTc interval. Serial serum bupropion levels peaked with the onset of cardiotoxicity (334 ng/mL) and fell into the therapeutic range within 24 h, which coincided with normalization of his ECG intervals. Levels of the metabolite hydroxybupropion peaked later (4302 ng/mL) and remained elevated even after neurological and cardiotoxic symptoms resolved. Discussion. Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion.     

Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone

BACKGROUND: Trimethoprim is a relatively selective inhibitor of the cytochrome P450 (CYP) 2C8 enzyme in vitro. Rifampin (INN, rifampicin) is a potent inducer of several CYP enzymes, and in vitro studies have suggested that it also induces CYP2C8. OBJECTIVE: Our aims were to investigate possible effects of trimethoprim and rifampin on CYP2C8 activity by use of rosiglitazone, a thiazolidinedione antidiabetic drug metabolized primarily by CYP2C8, as an in vivo probe. METHODS: Two separate randomized crossover studies with 2 phases were conducted. In study 1, 10 healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 4 days. On day 3, they ingested a single 4-mg dose of rosiglitazone. In study 2, 10 healthy volunteers took 600 mg rifampin or placebo orally once daily for 5 days. On day 6, they ingested a single 4-mg dose of rosiglitazone. In both studies, plasma rosiglitazone and N -desmethylrosiglitazone concentrations were measured for up to 48 hours. Results In study 1, trimethoprim raised the area under the plasma rosiglitazone concentration-time curve [AUC(0- infinity )] by 37% (range, 16% to 51%; P <.0001) and the peak plasma rosiglitazone concentration (C max ) by 14% (range, -3% to 38%; P =.0014). The elimination half-life (t 1/2 ) of rosiglitazone was prolonged from 3.8 to 4.8 hours ( P =.0013). Trimethoprim reduced the formation of N -desmethylrosiglitazone. In study 2, rifampin reduced the AUC(0- infinity ) and C max of rosiglitazone by 54% (range, 46% to 63%; P <.0001) and 28% (range, 2% to 56%; P =.0003), respectively. The t 1/2 of rosiglitazone was shortened from 3.8 to 1.9 hours ( P <.0001). Rifampin increased the formation of N -desmethylrosiglitazone. CONCLUSIONS: Trimethoprim raises and rifampin reduces the plasma concentrations of rosiglitazone by inhibiting and inducing, respectively, the CYP2C8-catalyzed biotransformation of rosiglitazone.     

Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19.

OBJECTIVE: Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N-demethylation. METHODS: A single oral 100-mg dose of sertraline was administered to 6 subjects who were extensive metabolizers and 6 subjects who were poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes were predetermined by polymerase chain reaction-based amplification, followed by restriction fragment length polymorphism analysis. Phenotypes were determined by use of the omeprazole metabolic rate. The plasma concentrations of sertraline and desmethylsertraline were determined by gas chromatography with electron-capture detection. RESULTS: Six poor metabolizers with m1 mutation had area under the plasma concentration versus time curve (AUC(0-infinity)) values (983.6 +/- 199.3 microg x h/L versus 697.6 +/- 133.0 microg x h/L; P <.05) and terminal elimination half-life values of sertraline (35.5 +/- 5.6 hours versus 23.5 +/- 4.4 hours; P <.01) that were significantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozygous for CYP2C19*1. The oral clearance of sertraline in poor metabolizers (105.3 +/- 19.4 L/h) was significantly lower than that of extensive metabolizers (148.4 +/- 28.6 L/h). The area under the concentration-time curve from 0 to 144 hours and the maximum plasma concentration of desmethylsertraline in poor metabolizers were significantly lower than the values of extensive metabolizers (627.6 +/- 203.8 microg x h/L versus 972.1 +/- 270.3 microg x h/L; P <.05; and 23.6 +/- 6.5 nmol/L versus 32.4 +/- 8.2 nmol/L; P <.01; respectively). CONCLUSIONS: The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of sertraline.