PHARMACOKINETIC ASSESSMENT OF THE HEPATIC AND INTESTINAL FIRST-PASS EFFECT OF S-ADENOSYLMETHIONINE IN RATS

The aim was to pharmacokinetic assess the hepatic and intestinal first-pass effect and the poten-tial mechanism of S-adenosylmethionine (SAMe) in rats. Different doses of SAMe were administered to rats via the duodenal, port vein, or peripheral femoral vein to assess the pharmacokinetic characteristics. Pretreatment with ketoconazole or verapamil to rats by the duodenal way separately, 30 min later, SAMe was administrated via the duodenal way. Similarly, SAMe was administrated via a peripheral femoral vein 30 min after pretreatment with ketoconazole or verapamil by the duodenal way. Plasma drug concentra-tion was determined by high-performance liquid chromatography. SAMe showed dose-dependent phar-macokinetic characteristics at different doses administrated via a duodenal, port, or peripheral femoral vein. Duodenal administration of 140 mg/kg SAMe, the bioavailability, hepatic and intestinal extraction ratio were 10.16 +/- 2.07%, 18.73 +/- 2.42% and 84.82 +/- 3.74%. After increased to 280 mg/kg, the values changed to 17.77 +/- 5.41%, 12.25 +/- 2.85% and 79.86 +/- 5.53%, respectively. Compared with the control group, pretreatment with ketoconazole or verapamil could significantly increase the value of AUC and the peak concentration (Cmax) of SAMe administered intraduodenally, while having no significant effects on intravenous pharmacokinetic parameters. In brief, SAMe showed a dose-dependent plasma concen-tration by the transintestinal or parenteral route and underwent a marked first-pass effect characterized by more extraction in the intestine than in the liver. Intestinal CYP3A4 mediated drug metabolism and P-glycoprotein mediated drug efflux may be involved in the intestinal first-pass extract of SAMe. Increas-ing the dose just mildly improves the bioavailability of SAMe, while inhibition of intestinal CYP3A4 and P-glycoprotein activity may be an effective means.

Automated summary

This study aimed to evaluate the hepatic and intestinal first-pass effect of S-adenosylmethionine (SAMe) in rats and explore its potential mechanism. The results showed that SAMe exhibited dose-dependent pharmacokinetic characteristics when administered via different routes, with higher extraction in the intestine than in the liver. Intestinal CYP3A4 and P-glycoprotein may be involved in the intestinal first-pass extraction of SAMe. Inhibition of intestinal CYP3A4 and P-glycoprotein activity may be an effective approach to improve the bioavailability of SAMe.