Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

Abstract

The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of nebicapone in rats and mice. Upon oral administration of nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat.Nebicapone was rapidly absorbed reaching plasma C max within 30 min and being completely eliminated by 8 h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K cat values, respectively 7.3 and 6.4 min -1 ), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83).Furthermore, nebicapone inhibited rat liver COMT with a lower K i than mouse liver COMT (respectively 0.2 versus 1.2 nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by nebicapone. The more pronounced inhibitory effects of nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by nebicapone than the former.

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

“…The HLMs or human expressed UGT enzymes were employed for kinetic studies at concentrations ranging from 0.0021 mg/mL to 0.0053 mg/mL. The rates of the glucuronidation were fitted to the following equations: Where V (nmol/mg/min) is the rates of the glucuronidation, C metabolite (μM) and C protein (mg/mL) respectively are the concentration of the metabolite and the reaction protein, t (min) is the reaction time [2,22]. …”

“…It exhibits a wide range of pharmacological effects, including antioxidation, anti-inflammation, and anticarcinogenic activity [2,3]. A study reported that after luteolin’s oral administration, it undergoes methylation as a major metabolic pathway.…”

Role of Catechol-O-Methyltransferase in the Disposition of Luteolin in Rats

“…Liver, kidney, small intestine (jejunum), and lung tissue homogenates were prepared as described previously (Bonifácio et al, 2009). In brief, six male Sprague-Dawley rats were sacrificed by cervical dislocation after fasting for 12 h. Tissues (liver, kidney, small intestine, and lung) were homogenized in phosphate buffer (5 mM, pH 7.4) and then were centrifuged at 15,000g for 20 min.…”

“…The COMT reaction was performed as described previously with some modifications (Bonifácio et al, 2009). In brief, the reaction mixture containing homogenate protein (1.0 mg/ml), 100 M MgCl 2 , 1.0 mM EGTA, and 20 M luteolin, with or without 30 nM entacapone in 150 l of phosphate buffer (5 mM, pH 7.8), was preincubated for 3 min at 37°C, and then 1.5 l of 25 mM S-adenosylmethionine dissolved in phosphate buffer (5 mM, pH 7.8) was added to initiated the reaction.…”

Development of a liquid chromatography assay for the determination of opicapone and BIA 9–1079 in rat matrices

“…The rat is the most frequently employed species for pharmacokinetic and pharmacodynamic nonclinical studies with COMT inhibitors (Wikberg and Taskinen, ; Wikberg et al ., ; Vieira‐Coelho and Soares‐da‐Silva, ; Parada et al ., ; Forsberg et al ., ; Soares‐da‐Silva et al ., ; Bonifácio et al ., ; Sun et al ., ) and, therefore, we selected it as the most relevant animal model. To the best of our knowledge, there are only two liquid chromatographic techniques published to quantify opicapone and its active metabolite (BIA 9–1079; Almeida et al ., ; Gonçalves et al ., ).…”