Pharmacokinetics of FCE 22101 in man following different modes of administration
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Twelve healthy volunteers received single iv doses of either 500 and 1000 mg or 750 and 1500 mg of the sodium salt of FCE 22101; in addition, five of the volunteers received a further dose of 2000 mg. In the second part of the study, 11 of the volunteers received 1000 mg doses of FCE 22101 in a four-way randomized fashion by iv bolus (1000 mg, with and without probenecid), im injection (1000 mg plus lignocaine) and a continuous infusion (280 mg/h) to steady state. All doses were well tolerated by the volunteers with no serious side effects and no significant haematological or biochemical changes following drug administration. Plasma and urine concentrations of FCE 22101, and in the cross-over study also its open ring metabolites P1 and P2, were determined by HPLC. Good linearity was observed between the peak plasma levels or AUC and the dose given. Plasma concentrations were fitted to a two-compartment model and the mean pharmacokinetic parameters determined after iv bolus were: Cmax 117 mg/l, T ½ β 36 min, Vss 181, AUC 2179 mg/min/l with urinary recoveries of FCE 22101 37%, P1 36% and P2 6%. With probenecid the values were Cmax 116 mg/l, T ½ β 47min, Vss 141, AUC 4540 mg/min/l and urinary recoveries of FCE 22101 20%, P1 40% and P2 7%. Following im injection the mean values were Cmax 15 mg/l, Tmax 30 min, Tmax 14 min, T ½ β 61 min, AUC 2117 mg/min/l and urinary recoveries of FCE 22101 33%, P1 37% and P2 6%. At steady state during continuous infusion, mean values were Css 12.7 mg/l, Vss 131 and T ½ β after steady state was 22 min. Although urinary recoveries varied widely between volunteers there was a tendency towards consistency of recovery within individual volunteers. We conclude that FCE 22101 is a well tolerated penem with pharmacokinetic properties broadly similar to those of other penem and carbapenem antibiotics.Keywords:
Probenecid
Bolus (digestion)
Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC-MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0-12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0-12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.
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OBJECTIVE To study the pharmacokinetics of combination tablets containing amlodipine besylate/atorvastatin calcium in healthy volunteers.METHODS Thirty healthy volunteers(half male-half female)were divided into three groups.Each ten volunteers received a different dose strengths combination tablets(amlodipine/atorvastatin 5 mg/ 10 mg,10 mg/ 10 mg,5 mg/ 20 mg),respectively.The plasma concentrations of amlodipine and atorvastatin were measured by a fully validated LC-MS/MS method.The pharmacokinetic parameters were calculated thereafter in order to study the pharmacokinetic charateristics of amlodipine and atorvastatin in human.RESULTS The following data were the main pharmacokinetic parameters.Amlodipine(5 mg/ 10 mg),Cmax(3.14±0.46)μg·L-1,AUC0-120(131±22);10 mg/10 mg,Cmax(6.85±1.17)μg·L-1,AUC0-120(327±110)μg·h·L-1;5 mg/ 20 mg,Cmax(3.11±0.47)μg·L-1,AUC0-120(130±16)μg·h·L-1;atorvastatin,5 mg/10 mg,Cmax(11.3±6.7)nμg·L-1,AUC0-120(133.8±93.3);10 mg/10 mg,Cmax(16.7±12.1)μg·mL-1,AUC0-120(107.7±60.4)μg·h·L-1;5 mg/20 mg,Cmax(15.0±9.4)μg·L-1,AUC0-120(147.3±59.3)μg·h·L-1.CONCLUSION In all the three dose groups,Cmax and AUC of amlodipine increased in a dose-dependent manner.Atorvastatin coincide with non-linear pharmacokinetic characteristics.
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Probenecid
Microdialysis
Antifolate
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Objective To investigate the pharmacokinetics of single dose pioglitazone hydrochloride tablets in Chinese healthy volunteers.Methods A single administration of 30 mg pioglitazone hydrochloride tablets was given to 24 healthy male volunteers.The concentration of pioglitazone and its two active metabolites(M-Ⅲ and M-IV)in human plasma were determined by HPLC-MS/MS.The main pharmacokinetic parameters were analyzed.Results The main pharmacokinetic parameters of pioglitazone were as follows:Cmax was(1504.9±447.8)ng·mL-1,tmax was(1.46±0.69)h,t1/2Ke was(7.58±3.21)h,AUC0-48 was(11.22±2.60)μg·h·mL-1.The main pharmacokinetic parameters of M-Ⅲ were as follows:Cmax was(249.4±82.7)ng·mL-1,tmax was(11.94±6.14)h,t1/2Ke was(20.09±4.13)h,AUC0-120 was(10.90 ±3.55)μg·h·mL-1.The main pharmacokinetic parameters of M-IV were as follows:Cmax was(487.2±108.6)ng·mL-1,tmax was(13.33±5.23)h,t1/2Ke was(21.07±3.99)h,AUC0-120 was(22.78 ±5.04)μg·h·mL-1.Conclusion The tmax of M-Ⅲ and M-IV was rough 12～13 h,the Cmax of M-Ⅲ and M-IV are 16% and 32% of Cmax of pioglitazone,respectively.the AUC0-120 of M-Ⅲ and M-IV are 97% and 203% of AUC0-48 of pioglitazone,respectively.
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An LC-MS/MS method was established for the determination of potassium oxonate(Oxo) in human plasma and urine,the pharmacokinetics of Oxo was investigated in advanced gastric cancer patients after single and multiple administration of tegafur,gimeracil and oteracil potassium capsule(S-1),and the situation of drug accumulation after multiple administration was evaluated.For multiple administration,12 gastric cancer patients were treated with S-1 according to the body surface area(BSA) as follows:for single administration,patients were treated with 60 mg S-1 after breakfast;for 28-day consecutive administration,a dose of 60 mg S-1 was treated after breakfast,and the dose of 60 mg after supper for BSA≥ 1.5 m2or 40 mg for 1.25 m2BSA1.5 m2 respectively.Then the Oxo concentration in human plasma and urine was determined,and the pharmacokinetic characteristics and drug accumulation were evaluated.The calibration curves of Oxo were linear over the concentration ranges of 2-400 ng/mL in plasma and 0.02-10 μg/mL in urine.After single-dose administration of S-1,(1.7±1.2)% of Oxo was excreted in the form of prototype in urine within 36 h.The main pharmacokinetic parameters were as follows:the cmax was(110.5±100.8) ng/mL,t1/2 was(3.4±1.4) h,tmax was(2.2 ±0.7) h,respectively.For the multiple administration,the css-av and degree of fluctuation(DF) of Oxo were(110.8±108.0) ng/mL and 2.4±0.8,respectively.In the 28-day consecutive regimen,no significant chang in pharmacokinetic characteristics or drug accumulation of Oxo was observed,the safty of that multiple administration of S-1 in clinical application was confirmed.Compared with the data in literatures,the main pharmacokinetic parameters of Oxo in Chinese patients proved to be similar with those in other races.
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Probenecid
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Probenecid
Glucuronide
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Elenbecestat (E2609) is a BACE inhibitor primarily metabolized by carboxylesterase 2 (CES2) and to lesser extent by CYP3A. Drug-drug interaction studies assessed the effects of itraconazole (strong CYP3A and CES2 inhibitor), rifampin (strong CYP3A inducer), and donepezil on elenbecestat pharmacokinetics, as well as the effects of elenbecestat on digoxin (Pgp substrate) pharmacokinetics. This open label study in healthy adult subjects was conducted in 3 parts. Part A: subjects received a single oral dose of elenbecestat 50 mg on day 1; from day 6 to 20, subjects received daily doses of either itraconazole 200 mg or rifampin 600 mg; with a second dose of elenbecestat 50 mg on day 14. Part B: subjects received digoxin 0.25 mg on day 1, elenbecestat 50 mg/day from day 7 to 20, and a second digoxin dose at day 14. Part C: a 3-way crossover study in which each subject received a single dose of elenbecestat 50 mg, elenbecestat 50 mg in combination with donepezil 10 mg, and elenbecestat 50 mg dosed 2 hours before donepezil 10 mg, according to a randomized treatment sequence with ≥21-day washout between treatments. Pharmacokinetic assessments of drugs, including elenbecestat and metabolites M1, M2, and M5, were conducted. Co-administration of elenbecestat and itraconazole resulted in increases in elenbecestat Cmax, AUC(0-inf), and t1/2 compared with administration of elenbecestat alone (Figures). The Cmax of all elenbecestat metabolites decreased with itraconazole co-administration. Co-administration of elenbecestat and rifampin resulted in relatively no change in Cmax or t1/2, a minor decrease in AUC(0-inf), along with pronounced decreases in M2 and M5. In Part B, elenbecestat and digoxin co-administration increased digoxin Cmax slightly, but no changes in overall systemic exposure (AUC) were observed. Co-administration of elenbecestat and donepezil at the same time resulted in non-clinically meaningful increases in Cmax and AUC(0-inf). However, no notable changes in elenbecestat exposure occurred when administered 2 hours before donepezil. Results indicate that itraconazole's interaction was primarily due to CES2 inhibition, therefore, no restrictions or dose adjustments are warranted for elenbecestat when co-administered with CYP3A inhibitors. Furthermore, no dose adjustments are necessary for elenbecestat when co-administered with Pgp substrates or donepezil. The effect of co-administered drugs on elenbecestat pharmacokinetics (expressed as 90% CI of geomean). Donepezil administered * concomitantly or **2 h postdose with elenbecestat Horizontal axis shows fold change in Cmax and AUC relative to control (elenbecestat alone). Note: Generic name elenbecestat is not fixed at this time. The effect of elenbecestat on pharmacokinetics of digoxin (expressed as 90% CI of geomean).
Crossover study
CYP3A
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