Absorption, distribution and excretion of3H-labeled cephaeline- and emetine-spiked ipecac syrup in rats

Abstract

The maximum plasma radioactivity levels of tritium (3H)-labeled cephaeline, (24.3, 28.7 and 40.6 ng eq./mL) were reached at 2.00-3.33 hours following oral dosing of ipecac syrup. The maximum plasma radioactivity levels of 3H-emetine (2.71, 6.47 and 9.62 ng eq./mL) were reached at 1.08-2.33 hours following ipecac syrup administration. The Cmax values of 3H-cephaeline were followed by a biexponential decrease with half-lives t 1/2(lambda z) of 3.45-9.40 hours. On the other hand, the t 1/2 (lambda z)of 3H-emetine were 65.4-163 hours, which revealed a biexponential decrease. The radioactivity of both tritium-labeled compounds was distrbuted maximally in most tissues at 24 hours. For 3H-cephaeline, the maximum radioactivity levels in tissues were approximately 100-150 times greater than in plasma. For 3H-emetine, the radioactivity levels in tissues were approximately 1000-3000 times greater than in plasma. Tissue radioactivity levels decreased at a substantially slower rate than that observed in plasma. Tissue radioactivity of 3H-emetine decreased more slowly than that of 3H-cephaeline. For 3H-cephaeline, the cumulative biliary excretion of radioactivity was 57.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity in these rats was 16.5% and 29.1%, respectively, of the dose at 48 hours following dosing. For 3H-emetine, the cumulative biliary excretion of radioactivity was 12.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity was 9.4% and 34.1%, respectively, of the administered dose at 48 hours. The radioactivity level of 3H-emetine remaining in the carcasses at 48 hours was equivalent to approximately 50% of the dose. A portion of each tritium-labeled compound was subjected to entero-hepatic circulation. Thus, the absorption rate of 3H-cephaeline and 3H-emetine was estimated to be approximately 70% on the basis of the data obtained from excretion studies. There was no difference in the absorption process between these two compounds. However, the difference was admitted in the biliary clearance, which is the main excretion route of both compounds. Delayed excretion of 3H-emetine may be primarily due to its resorption as related to entero-hepatic circulation and tissue retention. This study has determined the absorption, distribution and excretion of 3H-cephaeline and 3H-emetine in rats.

Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences

“…At 12 h (T max ) the concentration reached to maximum of 1.61 μM and then gradually decreased to 0.36 μM at 72 h which was still much higher than the EC 50 (7 nM) for inhibition of virus replication. This was in accordance with the previous study with Ipecac syrup that Emetine could be enriched in the tissues such as lung [16], which was especially important for the COVID-19 since the lung was the major target tissue of the SARS-CoV-2 virus. In mice a similar trend was observed and at 12 h the maxium concentration (1.8 μM) was reached in the lung and gradually decreased to 0.23 μM which was still 30-fold higher than the EC 50 for the inhibition of virus replication ( Fig.…”

“…In order to obtain an envision for the clinical translation, we then tried to examine the pharmacokinetic (PK) profiles of Emetine in the preclinical in vivo models. Although there has been some random PK studies either with Emetine itself or Ipecac syrup (containing Emetine) [ 15 , 16 ], in order to obtain the detailed PK spectrum, we first systematically investigated Emetine in different species including mice, rats and beagle dogs to depict an overall picture (Table 1 ). The results showed that in mice and rats, oral administration of Emetine reached maximum concentration (C max ) in the blood plasma in a relatively long time (T max : 1.67 h and 9 h for the mice and rats respectively).…”

Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses

“…In fact, another advantage of intramuscular over oral administration could be its greater uptake by the lungs. With radiolabeled emetine given by the oral route in rats, there was, at most time points, significantly (0.8-5.8 times) more emetine found in the liver than there was in the lungs [11]. Conversely, with radiolabeled emetine given by the intraperitoneal route in guinea pigs, the situation was reversed; at each time point, there was over twice as much emetine in the lungs than the liver [16].…”

“…In relation to the lungs, after 8 and 24 h, the concentration of emetine in the lungs is~173 and~294 times higher than in plasma, respectively, with the maximum recorded amount present in the lungs at the 24-h time period. High concentrations were also found in many other tissues, such as the liver, heart, and small and large intestines [11]. Similarly, studies in humans have strongly indicated that emetine quickly undergoes extensive distribution to the tissues [9], with slow excretion and detectable concentrations that may persist in the urine for 40-60 days after treatment has been ceased [12].…”

“…Similarly, a high distribution into the bones, as for bisphosphonates [29], would also be of little use in this scenario. Emetine has good radiolabeled studies [11,16] that clearly showed that not only was the bulk of the emetine distributed in the tissues, but also a significant portion went to the lungs.…”