Pharmacokinetics Of Buspirone Research Articles

A High-Performance Liquid Chromatography with Photodiode Array Detection Method for Simultaneous Determination of Three Compounds Isolated from Wikstroemia ganpi: Assessment of the Effects on Cytochrome P450-Mediated Metabolism In Vitro and In Vivo.

In natural products, the content and quality of the marker components differ depending on the part, production area, collection period, and extraction method; therefore, a standardized analysis method is required to obtain consistent results. This study developed a simultaneous analysis method for three marker components (7-methoxylutolin-5-O-glucoseide, pilloin 5-O-β-d-glucopyranoside, rutarensin) isolated and purified from Wikstroemia ganpi (W. ganpi). Simultaneous analysis was performed using high-performance liquid chromatography with photodiode array detection (HPLC-PDA) method that was validated according to the International Council for Harmonisation (ICH) guidelines. The developed analytical method exhibited linearity (r2 > 0.999), detection limits (0.72-3.34 μg/mL), and quantification limits (2.19-10.22 μg/mL). The relative standard deviation (RSD) value of intra- and inter-day precisions was less than 1.68%, and analyte recoveries (93.42-117.55%; RSD < 1.86%) were validated according to the analytical procedures, and all parameters were within the allowable range. Quantitative analysis of the three marker components from W. ganpi MeOH extract (WGM) showed 7-methoxylutolin-5-O-glucoseide with the highest content (51.81 mg/g). The inhibitory effects of WGM on cytochrome P450 (CYP) substrate drugs were further investigated. The in vitro study revealed that WGM inhibited the CYP3A-mediated metabolism of buspirone and that 7-methoxylutolin-5-O-glucoseide and pilloin 5-O-β-d-glucopyranoside inhibited the metabolism of buspirone with IC50 values of 2.73 and 18.7 μM, respectively. However, a single oral dose of WGM did not have significant effects on the pharmacokinetics of buspirone in rats, suggesting that WGM cannot function as an inhibitor of CYP3A-mediated metabolism in vivo.

The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects.

IntroductionA new combination tablet containing sublingual testosterone and oral buspirone (T+B) was developed to benefit a subgroup of women suffering from female sexual interest/arousal disorder, caused by dysfunctionally overactive sexual inhibition.AimThe aim of this study was to compare the effect of food intake on the pharmacokinetics of buspirone, administered as a dual-route, dual-release combination tablet containing 0.5 mg testosterone (T) and 10 mg buspirone (B).Methods19 healthy women took T+B under fed and fasted conditions during 2 overnight visits. The blood was sampled over a 24-hour period to determine the pharmacokinetics of buspirone and its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP). Total testosterone levels were also assessed, at 5 time points and for quality control purposes only, as sublingual testosterone uptake is not expected to be influenced by prior food intake.Main Outcome MeasurePK profiles of buspirone and 1-PP.ResultsFor buspirone, the 90% confidence intervals (CIs) of the observed fed/fasted ratios for the plasma area under the curve (AUC)0-last, AUC0-inf, and Cmax after administration of T+B were not contained within the prespecified bounds of 80% and 125%, except for the lower bound of AUC0-inf. However, the 90% CIs of the observed fed/fasted ratios for the plasma AUC0-last, AUC0-inf, and Cmax of 1-PP were contained within the prespecified bounds, with the exception of the upper bound for Cmax. The mean AUCs and Cmax for 1-PP did not differ between fed and fasted conditions.ConclusionsAdministration of T+B after high-caloric food intake increased the bioavailability of buspirone but did not result in differences in Tmax when compared with fasted conditions. Both in fed and fasted conditions, T+B was generally well tolerated and safe. Exposure of 1-PP in fed and fasted conditions was comparable in both conditions. These results demonstrate that T+B can safely and effectively be used in both fed and fasted states.Gerritsen J, Bloemers J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects. J Sex Med 2020;8:186–194.

Modulation of Cytochrome P450 Activity by 18β-Glycyrrhetic Acid and its Consequence on Buspirone Pharmacokinetics in Rats.

The aim of this study was to elucidate the inhibition mechanism of 18β-glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC50 of 20.1 ± 10.7 μM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration-time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12-1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A-mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A-mediated drug metabolism in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

Modulation of Hepatic Cytochrome P450 Enzymes by Curcumin and its Pharmacokinetic Consequences in Sprague-dawley Rats.

Background:Curcumin (CUR) is a polyphenolic component derived from an herbal remedy and dietary spice turmeric (Curcuma longa).Objective:The aim of this study was to investigate inhibitory effects of CUR on in vitro cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single CUR dose in rats.Materials and Methods:An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral CUR in rats.Results:In the in vitro CYP inhibition study, CUR inhibited the CYP3A-mediated metabolism of testosterone (TES) with a half maximal inhibitory concentration of 11.0 ± 3.3 μM. However, the impact of a single oral CUR dose on the pharmacokinetics of BUS in rats is limited, showing that CUR cannot function as an inhibitor for CYP3A-mediated drug metabolism in vivo.Conclusion:To the best of our knowledge, our results are the first reported data regarding the inhibition of in vitro CYP3A-mediated metabolism of TES and the in vivo impact of a single CUR dose on the pharmacokinetics of BUS in rats. Further study is required to draw a confirmative conclusion on whether CUR can be a clinically relevant CYP3A4 inhibitor.SUMMARY CUR can inhibit the in vitro CYP3A-mediated metabolism of TES in RLM. However, the impact of a single oral CUR dose on the pharmacokinetics of BUS in rats is limited, showing that CUR cannot function as an inhibitor for CYP3A-mediated drug metabolism in vivo.

The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography–tandem mass spectrometric method of a specific probe buspirone

Aconitum species are widely used to treat rheumatism, cardiovascular diseases, and tumors in China and other Asian countries. The herbs are always used with drugs such as paclitaxel. Aconitine (AC) is one of the main bioactive/high-toxic alkaloids of Aconitum roots. AC is metabolized by cytochrome P450 (CYP) 3A. However, whether AC inhibits/induces CYP3A, which causes drug–drug interaction (DDI) is unclear. Our study aims to explore the potent effects of AC, as a marker component of Aconitum, on CYP3A using the probe buspirone in rats. The effects of oral AC on pharmacokinetics of buspirone were evaluated. CYP3A activity and protein levels in rat liver microsomes pretreated with oral AC were also measured using in vitro buspirone metabolism and Western blot. Buspirone and its major metabolites 1-(2-pyrimidinyl)piperazine and 6′-hydroxybuspirone were determined using a newly validated UPLC–MS/MS method. Single dose and 7-day AC administration at 0.125mg/kg had no effect on CYP3A activity since no change in the formation of 1-(2-pyrimidinyl)piperazine and 6′-hydroxybuspirone. CYP3A activity and protein levels in liver microsomes were also not affected by 7-day AC pretreatment at 0.125mg/kg. Therefore, AC neither inhibits nor induces CYP3A in rats, indicating AC does not cause CYP3A-related DDI in the liver.

Pharmacokinetics of Buspirone in Autistic Children

Buspirone is used to treat generalized anxiety disorder in children and may be useful in developmental disorders in which brain serotonin synthesis is altered. Autistic children (13 boys, 7 girls) were given a single oral dose of 2.5 mg (2-3 years) or 5.0 mg (4-6 years). Blood was collected for 8 hours, and plasma was assayed for buspirone and its metabolite 1-pyrimidinylpiperazine (1-PP). The peak concentration of buspirone averaged 1141 +/- 748 pg/mL with a time to maximum concentration of 0.8 hours. Half-life was 1.6 +/- 0.3 hours. Peak concentrations of 1-PP were 4.5-fold higher than for buspirone. Girls had higher peak concentrations (1876 vs 746 pg/mL) for buspirone and a lower peak 1-PP/buspirone concentration ratio. These results suggest that buspirone is rapidly absorbed and eliminated in young children with extensive metabolism to 1-PP. Plasma concentrations with 2.5- to 5.0-mg doses were similar to those observed in older children receiving 7.5- to 15-mg doses.

Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats.

The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokinetic-pharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with set-point control. Both buspirone and 1-PP behaved as partial agonists relative to R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine(1A) agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.

Pharmacokinetics of buspirone following oral administration to rhesus monkeys.

Pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinyl piperazine (1-PP) following oral administration were assessed in rhesus monkeys at doses used in chronic toxicology studies. The study was conducted over four periods in three male and three female rhesus monkeys. In the first three periods, buspirone hydrochloride solution was administered in a randomized manner by oral gavage at doses (expressed as buspirone free base) of 12.5, 25 and 50 mg kg(-1) once a day on days 1 and 7 and twice a day on days 2-6. In the last period, all monkeys received 25 mg kg(-1) buspirone as a single daily dose for 7 days. Serial plasma samples were collected for analysis of buspirone and 1-PP on days 1 and 7 in the first three periods and on day 7 in the last period for assessment of single dose and steady-state pharmacokinetics. Inter-animal variability in the pharmacokinetics of buspirone was high. Examination of Cmin vs time plots revealed that the steady state was attained by day 7 except for one monkey who demonstrated much higher Cmin values. For buspirone, dose proportionality was concluded for both Cmax and AUC on day 1 but not on day 7. The accumulation factor on day 7 for buspirone was nearly 5 for Cmax and 7 for AUC when compared with day 1. For 1-PP, dose proportionality was concluded except for Cmax in male monkeys on day 7. In contrast to buspirone, 1-PP showed less than 2-fold accumulation in Cmax and AUC values on day 7 compared with those on day 1. Exposure at a dose of 25 mg kg(-1) once daily was in between the 125 mg kg(-1) and 25 mg kg(-1) twice-a-day regimens. These results document dose-dependency in the steady-state pharmacokinetics of buspirone in rhesus monkeys.

Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug.

Buspirone is an anxiolytic drug given at a dosage of 15 mg/day. The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors. Following a oral dose of buspirone 20 mg, the drug is rapidly absorbed. The mean peak plasma concentration (Cmax) is approximately 2.5 micrograms/L, and the time to reach the peak is under 1 hour. The absolute bioavailability of buspirone is approximately 4%. Buspirone is extensively metabolised. One of the major metabolites of buspirone is 1-pyrimidinylpiperazine (1-PP), which may contribute to the pharmacological activity of buspirone. Buspirone has a volume of distribution of 5.3 L/kg, a systemic clearance of about 1.7 L/h/kg, an elimination half-life of about 2.5 hours and the pharmacokinetics are linear over the dose range 10 to 40 mg. After multiple-dose administration of buspirone 10 mg/day for 9 days, there was no accumulation of either parent compound or metabolite (1-PP). Administration with food increased the Cmax and area under the plasma concentration-time curve (AUC) of buspirone 2-fold. After a single 20 mg dose, the Cmax and AUC increased 2-fold in patients with renal impairment as compared with healthy volunteers. The Cmax and AUC were 15-fold higher for the same dose in patients with hepatic impairment compared with healthy individuals. The half-life of buspirone in patients with hepatic impairment was twice that in healthy individuals. The pharmacokinetics of buspirone were not affected by age or gender. Coadministration of buspirone with verapamil, diltiazem, erythromycin and itraconazole substantially increased the plasma concentration of buspirone, whereas cimetidine and alprazolam had negligible effects. Rifampicin (rifampin) decreased the plasma concentrations of buspirone almost 10-fold.

Clinical pharmacokinetics of oral buspirone in patients with impaired renal function.

12 patients with mild to moderate impairment of renal function and 12 healthy subjects each received 20mg buspirone as a single dose in this acute study. Six anuric patients with chronic renal failure were given two 20mg doses of buspirone, the first 2 days before haemodialysis (between dialyses) and the second during hemodialysis (2 hours before dialysis began). The differences between the median pharmacokinetic values of buspirone for healthy subjects, patients with mild to moderate renal impairment, and anuric patients were not statistically significant. Similarly, there were no significant differences between values in mild to moderate renal failure vs healthy subjects. Some of the median pharmacokinetic values for the active buspirone metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), however, differed significantly for anuric patients, compared with healthy subjects or patients with mild to moderate renal impairment. When assessed between and during haemodialysis, the anuric patients had significantly (p less than 0.05) greater pharmacokinetic median values: half-life (t 1/2) = 15.2 vs 9.8 hours; area under the concentration-time curve (AUC) = 604 vs 404 nmol/L.h; and mean residence time (MRT) = 9.28 vs 6.96 hours. No firm recommendation for specific dosage can be made based on the present data. However, it does appear that in patients with mild to moderate renal impairment, the pharmacokinetics of buspirone and its active metabolite 1-PP are similar to those in individuals with normal renal function. For anuric patients higher concentrations of the 1-PP metabolite are attained while they are not undergoing haemodialysis. A dosage reduction of 25 to 50% might be necessary when buspirone is given to anuric patients.

Pharmacokinetics of buspirone as determined by ex vivo (3H)-DPAT binding

Ex vivo (3H)-8-hydroxy-2-(di-n-propylamino)-tetraline ((3H)-DPAT) binding to the hippocampus has been utilized to determine the pharmacokinetic parameters of buspirone after i.v. (30 umol/kg) and oral (100 umol/kg) administration of this drug to rats. Intravenous buspirone rapidly penetrated the brain as demonstrated by a maximum inhibition of (3H)-DPAT binding at 1 min. Elimination of drug from the brain was biphasic, with a first component half-life of 24.8 min and a second component half-life of 96 min. Oral buspirone at 3 times the i.v. dose produced less than one-third the maximum inhibition of (3H)-DPAT binding compared to that observed with i.v. buspirone. The pharmacokinetic parameters of buspirone observed in the present study are in agreement with those reported previously. Thus, the ex vivo binding assay could be utilized to determine the bioavailability of the drug to the brain, and its duration of action.

Effects of Buspirone and Diazepam, Alone and in Combination with Alcohol, on Skilled Performance and Evoked Potentials

Effects of buspirone, 10 and 20 mg, and diazepam, 10 mg, on skilled performance and evoked responses, as well as their interactions with 0.8 g/kg of alcohol were investigated in 24 healthy men. Alcohol, 0.8 g/kg, caused the greatest performance impairment, followed closely by diazepam. Both doses of buspirone had lesser effects. Buspirone had primarily sedative effects which were short lasting, whereas diazepam impaired tracking and body balance in addition to being sedative. Both anxiolytics showed only slight additive interactions with the present dose of alcohol. A strong drug effect and a lesser but significant alcohol and a drug/alcohol interaction effect were seen on evoked potentials. Diazepam effects on evoked potentials were similar to alcohol, whereas buspirone in some instances appeared to reverse the alcohol effect. Pharmacokinetics of buspirone and diazepam were not significantly affected by concomitant administration of alcohol. The psychomotor side effect profile of a single anxiolytic dose of buspirone is preferable to a single 10-mg dose of diazepam.

Metabolism and disposition of buspirone

The metabolism and disposition of buspirone have been studied in the rat, the monkey, and in more than 150 human subjects. Buspirone is well absorbed, but is subject to first-pass metabolism. The mean systemic availability is approximately 4 percent. Buspirone is eliminated primarily by oxidative metabolism, which produces several hydroxylated metabolites, including 5-hydroxy-buspirone and 1-pyrimidinylpiperazine. The latter metabolite is from 1 to 20 percent as potent as buspirone in a variety of pharmacologic tests; 5-hydroxybuspirone is essentially inactive. In humans, the systemic exposure to buspirone increases linearly in relation to the oral dose. Food increases the bioavailability of buspirone by decreasing first-pass metabolism; absorption is not markedly altered. The pharmacokinetics of buspirone were not significantly different in men and women or in individuals 21 to 40 years old compared with those over 65 years of age. Half-life values observed in healthy volunteers ranged from two to 33 hours. Mean half-life values observed in healthy volunteers in the 14 studies conducted to date ranged from 2 ± 1 to 11 ± 3 hours. The half-life in women tended to be slightly longer than in men, but the difference was not significant. Hepatic cirrhosis resulted in a marked decrease in the clearance of buspirone, which correlated with serum alkaline phosphatase activity. Renal disease produced a modest decrease in buspirone clearance, which could not be correlated with an objective clinical measurement reflecting the severity of renal impairment. Buspirone was not removed by hemodialysis. Buspirone is highly protein bound (more than 95 percent), interacting with both albumin and alpha-acid glycoprotein. However, buspirone did not displace dilantin, propranolol, digoxin, or warfarin from plasma proteins. In rats, buspirone neither inhibited nor induced hepatic mixed-function oxidases. Co-administration of buspirone with amitriptyline or diazepam did not alter the disposition of these agents or their demethylated metabolites.