Blood‐to‐muscle distribution and urinary excretion of higenamine in rats

Abstract

Higenamine is a β2‐agonist that has been prohibited in sports by the World Anti‐Doping Agency. Higenamine could potentially promote anabolism and lipolysis; however, its crucial pharmacokinetics data, particularly muscle distribution, remain unavailable. The present study aims to investigate the blood‐to‐muscle distribution as well as the urinary excretion of higenamine in laboratory rats. In the first experiment, the microdialysis technique was employed to continuously measure free, protein‐unbound concentrations in blood and muscle for 90 min (sampling at a 5‐min interval) after rats received IV infusion of higenamine. The mean half‐lives of higenamine in blood and muscle were 17.9 and 19.0 min, respectively. The blood‐to‐muscle distribution ratio (AUCmuscle/AUCblood) of higenamine was estimated to be 22%. In the second experiment, rats were orally administered with a single‐dose higenamine, and their urine samples were profiled at a 12‐h interval for up to 48 h. Results showed only a small portion of total consumption (1.44%, ranging 0.71%–2.50%) was excreted in the urine. Among these time points, about 43% cumulative amount of higenamine was eliminated within the first 12 h. Our data suggested that one‐quarter of the unbound higenamine rapidly penetrates from the vessels into muscle, distributes to the interstitial fluid, then eliminates from the rat in a short span of time. The muscle tissue is likely to have a low binding affinity for higenamine, and renal excretion plays a minor role in its elimination. Together, our findings provide valuable pharmacokinetics data that may gain deeper insights into higenamine's role in skeletal muscle functions.

Annual banned‐substance review: Analytical approaches in human sports drug testing 2020/2021

“…While AAFs associated with salmeterol have been extremely rare, 116 the number of higenamine findings has been substantial, and assessing the substance's pharmacological characteristics that contribute to its renal elimination was further investigated using an animal model. Chang et al 90 studied the blood-to-muscle distribution of higenamine after intravenous application of the β 2 -agonist in rats, which demonstrated a low binding affinity of higenamine to muscle tissue but a similar ratio (AUC muscle /AUC blood ) of 22% as observed also for clenbuterol. Further, upon oral administration of higenamine, the earlier reported very low bioavailability was corroborated, which concurs with the observations of Rasic et al, 140 who analyzed the effect of a 21-day application study with 75 mg of orally administered higenamine.…”

Pharmacological effects of higenamine based on signalling pathways and mechanism of action

“…The half-lives of HG in rat, rabbit and human blood are approximately 8 min ( Feng et al, 2012 ), 22 min ( Lo and Chen, 1996 ) and 18–27 min, respectively ( Wang et al, 2020 ; Chang et al, 2021 ). In a study, the average human clearance of HG was 249 L/H, renal clearance was 22.9 L/H, non-renal clearance was 226.1 L/H and the average recovery rate in urine within 8 h was 9.3%, suggesting that HG is not metabolised by the kidney but by the liver ( Feng et al, 2012 ).…”

“…A study on rats reported that 22% of HG penetrated from the blood vessels to the muscle tissue and was distributed to the interstitial fluid after an intravenous infusion of 10 mg/kg HG, which was quickly eliminated in approximately 90 min. The half-life of HG in the muscle tissues was approximately 19 min ( Chang et al, 2021 ). However, the metabolism of HG in human muscle tissues has not been investigated.…”

“…To prevent side effects owing to its toxic metabolites, the dosage of Fuzi should be carefully adjusted. HG is listed as an ingredient in over-the-counter weight loss and sports supplements in countries such as the United States of America; however, it is commonly used as a traditional Chinese medicine formulation in China ( Cohen et al, 2019 ; Chang et al, 2021 ). HG is a benzylisoquinoline alkaloid with various pharmacological effects, including vasodilation, anti-platelet activity and calcium channel-blocking activity ( Chang et al, 1994 ).…”