Possible differential induction of phase 2 enzyme and antioxidant pathways by american ginseng, Panax quinquefolius.

Human immunodeficiency virus (HIV)-infected patients often take herbal medicines, which may interact with antiretrovirals. American ginseng induces phase 2 and antioxidant enzymes in vitro and might increase the clearance of zidovudine and/or enhance antioxidant activity. Ten healthy volunteers received 300 mg of zidovudine orally before and after 2 weeks of treatment with a ginsenoside-enriched American ginseng extract 200 mg twice daily. This ginseng extract induced the phase 2 enzyme quinone reductase with an average concentration of doubling of enzyme activity of 190 microg/mL. Total ginsenoside content was 8.5 +/- 0.5%. Pharmacokinetic profiles of zidovudine and oxidative stress marker concentrations were measured post-zidovudine dose. American ginseng does not significantly affect the formation clearance of zidovudine to its glucuronide (ratio post- to pre-American ginseng = 1.17; 90% confidence interval: 0.95-1.45; P = .21), total clearance (ratio = 0.97; 0.82-1.14; P = .70), or plasma zidovudine AUC0-8 (ratio = 1.03; 0.87-1.21; P = .77). Oxidative stress biomarkers are reduced post-American ginseng (F2-isoprostane ratio = 0.79; 0.72-0.86; P < .001; 8-hydroxy-deoxyguanosine ratio = 0.74; 0.59-0.92; P = .02). Two weeks of American ginseng does not alter zidovudine pharmacokinetics but reduces oxidative stress markers.

Effects of smoking cessation, acute re-exposure and nicotine replacement in smokers on AIR inhaled insulin pharmacokinetics and glucodynamics.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers. WHAT THIS STUDY ADDS: * This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR((R)) inhaled insulin pharmacokinetics and glucodynamics. * We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable. * Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response. AIMS: To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT). METHODS: Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8-12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD. RESULTS: Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced. CONCLUSION: Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.

Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects.

AIMS: To compare single- and multiple-dose duloxetine pharmacokinetics between healthy Japanese and Caucasians. METHODS: Twenty-four subjects of each race were given single oral doses of duloxetine (20, 40 and 60 mg) in a randomized, double-blind study. Another 20 subjects of each race received 20, 40 mg or placebo (2 : 2 : 1) twice-daily for 5 days. RESULTS: Following single doses, the mean duloxetine C(max) and AUC were approximately 20% greater in Japanese. This difference could be explained by the 15% lower average body weight in Japanese. Similar results were observed following multiple dosing. CONCLUSION: Duloxetine pharmacokinetics are not meaningfully different between Japanese and Caucasians.

Effects of chronic renal failure on the pharmacokinetics of ruboxistaurin and its active metabolite 338522.

BACKGROUND: Ruboxistaurin, a specific inhibitor of the beta(1) and beta(2) isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route. OBJECTIVE: To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522. METHODS: Six healthy subjects (creatinine clearance >80 mL/min/1.73 m(2)) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32 mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis. RESULTS: No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)], maximum plasma concentration [C(max)] and elimination half-life [t(1/2)]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p=0.163). Ruboxistaurin was well tolerated in both groups of subjects. CONCLUSION: These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.

Effect of exenatide on the steady-state pharmacokinetics of digoxin.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Clinical pharmacokinetics of alamifovir and its metabolites.

Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclinical efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single- and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.2 to 80 mg), with a subset receiving 20 mg in a fed state. Study 2 subjects were dosed with 2.5 to 15 mg twice daily for 15 days. Plasma samples were collected over 72 h in study 1 and over 24 h on days 1 and 15 in study 2. Concentrations of alamifovir and its major metabolites were determined using liquid chromatography/tandem mass spectrometry methods. The data were analyzed using a noncompartmental technique. Although alamifovir was rapidly absorbed, there was limited systemic exposure due to its rapid hydrolysis and formation of at least three metabolites, suggesting that alamifovir acts as a prodrug. The major metabolites detected were 602074 and 602076, with 602075 detectable only in higher-dose groups. Maximum 602074 plasma concentration was achieved at approximately 0.5 h (T(max)) and declined with a 1- to 2-h terminal half-life (t(1/2)). Maximum concentrations of 602076 (C(max)) averaged 10% of the 602074 C(max) and reached T(max) in 2.5 h with a 4-h t(1/2). Food appeared to decrease the extent of absorption of the compound. Multiple dosing resulted in minimal accumulation, and the concentrations following multiple doses could be predicted using the single-dose data. Alamifovir was well tolerated and the pharmacokinetics were characterized in these studies.

Development and validation of a liquid chromatography-tandem mass spectrometric method for the determination of alpha-methyltyrosine in human plasma.

A sensitive and selective LC-MS-MS method for the isolation and quantification of alpha-methyltyrosine (AMT) from human plasma is described. The method employs a simple protein precipitation using zinc sulfate and sodium hydroxide. This precipitation procedure produced samples with high aqueous content that could be directly injected into a LC-MS-MS system without compromising reverse-phase chromatographic performance. Chromatographic separation was performed on a MetaChem MonoChrom C(18) column (2.0 mm x 50 mm; 5 microm) at a flow rate of 1 mL/min. Compounds were eluted using a gradient mixture of water-acetic acid (100:0.1, v/v) and acetonitrile-acetic acid (100:0.1, v/v). The structural analog alpha-hydroxymethyltyrosine was used as the internal standard. Mass spectrometric detection was carried out with a triple quadrupole mass spectrometer. The method was validated and used to determine human plasma AMT concentrations, and has been implemented to derive pharmacokinetic parameters.

Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers.

AIM: To investigate the effect of duloxetine on the pharmacokinetics and tolerability of tolterodine and its active 5-hydroxymethyl metabolite (5-HM). METHODS: Sixteen healthy subjects received two 5-day treatment regimens in a randomized, double-blinded, crossover fashion: tolterodine (2 mg, BID) + duloxetine (40 mg, BID), tolterodine (2 mg, BID) + duloxetine placebo (BID). Plasma concentrations of tolterodine and 5-HM were measured on day 5. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. RESULTS: Duloxetine increased the AUC(tau,ss) of tolterodine by 71%[geometric mean, 95% confidence interval (CI) 31, 123], and its C(max,ss) by 64% (CI 30, 106), and prolonged its t(1/2) by 14% (CI 1, 28). Duloxetine did not affect the plasma concentrations or t(1/2) of 5-HM. Laboratory data and vital signs did not reveal any clinically significant changes or abnormalities. CONCLUSIONS: Duloxetine exhibited minor inhibitory effects on the pharmacokinetics of tolterodine but not 5-HM. Coadministration of these drugs was well tolerated and demonstrated no significant safety findings in the studied population. These findings suggest that there should not be a need for routine adjustment of tolterodine dosage in the presence of duloxetine.

Olanzapine pharmacokinetics are similar in Chinese and Caucasian subjects.

AIM: To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects. METHODS: Randomized, three-period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived. RESULTS: No statistically significant racial differences in the weight-normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5- and 10-mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups. CONCLUSION: The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.

Quinidine does not affect the renal clearance of moxonidine.

AIMS: To test the hypothesis that the renal clearance of moxonidine decreases when dosed with quinidine. METHODS: A randomized, two-period study was conducted with six healthy, male subjects orally dosed with either 0.2 mg moxonidine alone or 1 h after 400 mg quinidine sulphate. Pharmacokinetic parameters were calculated using a noncompartmental analysis method. RESULTS: When coadministered, quinidine significantly increased moxonidine AUC and t1/2 by 11% and 15%, respectively, and decreased CL/F by 10% compared with the control dosing. CLR and Aeur were not significantly different. Clinically, both treatments were well tolerated. CONCLUSIONS: Quinidine does not affect the renal clearance of moxonidine. The decrease in apparent total clearance of moxonidine with quinidine coadministration was possibly due to metabolic inhibition, though not likely to be clinically significant.