Pharmacokinetics, Safety, and Tolerability of Amygdalin and Paeoniflorin After Single and Multiple Intravenous Infusions of Huoxue-Tongluo Lyophilized Powder for Injection in Healthy Chinese Volunteers.

PURPOSE: Huoxue-Tongluo lyophilized powder for injection (HTLPI), a traditional Chinese medicine preparation, is a compound of Persicae semen and Paeoniae Radix Rubra that is used mainly for treating blood-stasis obstruction syndrome in the acute stage of cerebral ischemic stroke. Amygdalin (AD) and paeoniflorin (PF) are 2 typical bioactive components in HTLPI and were selected as indicators for this pharmacokinetic study of HTLPI. The objective of this study was to investigate the safety profile, tolerability, and pharmacokinetic properties of AD and PF after single and multiple intravenous infusions of HTLPI in healthy Chinese volunteers. METHODS: Twenty-one healthy Chinese subjects were recruited for this open-label, single ascending-dose (3, 6, and 9 g) and multiple-dose (6 g, once daily) study. Safety profile was assessed by adverse events and physical examination throughout the study. Serial plasma and urine samples were analyzed by HPLC-MS/MS. Pharmacokinetic parameters of AD and PF were calculated using noncompartmental analysis. FINDINGS: In the single-dose phase of the study, the mean maximum plasma concentration and the mean area under the plasma concentration-time curve of AD and PF increased proportionally with each dose escalation. In the multiple-dose phase, the steady state was achieved by day 4 after multiple-dose administration of 6 g HTLPI. Mean pharmacokinetic parameters achieved on day 1 were similar to those on day 7. No significant accumulation was observed after repeat doses of 6 g HTLPI. Approximately 79.6% of the administered AD and 48.4% of the administered PF were excreted unchanged in urine within 24 hours. No serious adverse events were observed during the entire study. IMPLICATIONS: The pharmacokinetic properties of AD and PF were linear after a single intravenous infusion of HTLPI in the dose range of 3-9 g. No systemic accumulation was observed with repeat doses of HTLPI. Sex had no significant effect on the pharmacokinetic properties of AD and PF. Intravenous infusion of HTLPI was well tolerated in healthy Chinese subjects.

Influence of genetic polymorphisms on the pharmacokinetics of celecoxib and its two main metabolites in healthy Chinese subjects.

Celecoxib is a selective cyclooxygenase-2 inhibitor used extensively for the treatment of rheumatism and osteoarthritis. The aim of this study was to evaluate the influence of the genetic polymorphisms of CYP2C9, CYP2D6 and CYP3A4 on the pharmacokinetics (PK) of celecoxib and its two main metabolites, hydroxyl-celecoxib and carboxy-celecoxib, in healthy Chinese subjects, based on a bioequivalence study of celecoxib. This study was an open-label, two-period, crossover study. 52 healthy Chinese male subjects were recruited and were genotyped for CYP2C9*3, CYP2C9*13, CYP2D6*10 and CYP3A4*18 by using polymerase chain reactions (PCR). They were randomly divided into two groups and each group received either 200mg test formulation followed by reference formulation or vice versa with a one-week washout period. Safety and tolerability were monitored throughout the study and no severe adverse events were observed. Genotyping using PCR revealed that none of the subjects carried the CYP3A4*18 and CYP2C9*13. Therefore, the influence of the CYP2C9*3 and CYP2D6*10 on the PK of celecoxib and its metabolites in Chinese was studied. Compared with CYP2C9*1/*1 group, pharmacokinetic parameters of celecoxib such as AUC0-48 and Cmax was increased by 90.6% and 45.8%, the t1/2 was extended by 21.8% and the CL/F was decreased by 51.1% in CYP2C9*1/*3 group. In terms of hydroxy-celecoxib, compared with CYP2C9*1/*1 group, the Cmax was decreased by 17.2%, the t1/2 prolonged 42.1% in CYP2C9*1/*3 group. In terms of carboxy-celecoxib, the AUC0-48 was increased by 25.2%, the t1/2 prolonged 16.1% and the CL/F was decreased by 21.2% in CYP2C9*1/*3 group. Except for the t1/2 of hydroxy-celecoxib, no statistically significant difference was observed in other pharmacokinetic parameters of hydroxy-celecoxib and carboxy-celecoxib between the two CYP2C9 genotypic groups. This study revealed that there was no significant influence of CYP2D6*10 on the metabolism of celecoxib, and the expression of CYP2C9*3 led to increased drug exposure and slowed drug disposition in healthy Chinese male subjects.

Gradient elution mode for the troubleshooting of matrix effect on the determination of G004 in different tissues by LC-MS/MS.

A steep gradient elution mode was applied to reduce the risk of matrix effect (ME) for the determination of G004, a novel sulfonylurea hypoglycemic drug, in a tissue distribution study by LC-MS/MS. The mass spectra of the total-ion-current chromatograms combined with the post-column infusion traces enabled the 'unseen' interfering species to be directly detected, and ensured that the chromatography conditions and sample preparation method were adequate to overcome the ME. According to this, a steep gradient elution mode was designed to overcome the intense ME from different tissues. The analysis was performed by monitoring the transitions m/z 558.1 → 419.0 for G004 and m/z 489.3 → 364.1 for glimepiride used as the internal standard. Calibration curves recovered over a range from 0.1 to 10000 ng/mL for seven different tissues. Sex-related difference was found in the tissue distribution. The drug levels in the tissues of female rats were about two to three times higher than those in male counterparts. The highest level was observed in liver, then in kidney, heart, pancreas, lung and spleen, but no G004 was detected in brain. G004 was slowly eliminated from female rats compared with male rats. There was no long-term accumulation of G004 in male or female rat tissues.

Pharmacokinetics of levosulpiride after single and multiple intramuscular administrations in healthy Chinese volunteers.

The main purpose of this study was to evaluate the pharmacokinetics of levosulpiride in humans after single and multiple intramuscular injections. Six males and six females received single dose of either 25 mg or 50 mg levosulpiride, or multiple doses of 25 mg every 12 h for 5 consecutive days. In the single 25 mg study, the mean peak plasma concentration (C max) was 441 ng/mL, the mean area under the concentration-time curve from 0 to 36 h (AUC0-36) was 1724 ng h/mL, and the mean elimination half-life (t 1/2) was 7.0 h. In the single 50 mg study, the mean C max was 823 ng/mL, the mean AUC0-36 was 3748 ng·h/mL, and the mean t 1/2 was 6.8 h. After multiple doses of 25 mg levosulpiride, the average plasma concentration (C av) was 136 ng/mL, the fluctuation index (DF) was 3.60, and the accumulation ratio (R) was 1.2. Levosulpiride injections appeared to be well tolerated by the subjects, and can be used for successive administration.