Preclinical Pharmacokinetics and Pharmacodynamics of Coptidis Preparation in Combination with Lovastatin in High-Fat Diet-Induced Hyperlipidemic Rats

Abstract

Lovastatin is a standard therapy for dyslipidemia. Alternatively, some ethnomedicines, such as Coptidis preparation, have been used for the treatment of dyslipidemia. Statins and complementary and alternative medicines may possess individual mechanisms of action against dyslipidemia. We hypothesize that the combination of Coptidis preparation and lovastatin may have synergistic effects for the treatment of dyslipidemia. To investigate this hypothesis, we developed a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method to monitor lovastatin and its metabolites for pharmacokinetic studies in rats. This study was divided into four groups: lovastatin (10 mg/kg, p.o.) alone and lovastatin (10 mg/kg, p.o.) + Coptidis preparation (0.3, 1, or 3 g/kg, p.o.) for five consecutive days. In pharmacodynamic studies, a high-fat diet (HFD) was used to induce dyslipidemia in experimental rat models. The HFD rats were divided into four groups: treatment with HFD, HFD + lovastatin (100 mg/kg, p.o.), HFD + Coptidis preparation (1 g/kg, p.o.), and HFD + lovastatin (50 mg/kg, p.o.) + Coptidis preparation (1 g/kg, p.o.) for 28 consecutive days. The pharmacokinetic results demonstrated that Coptidis preparation significantly augmented the conversion of lovastatin into its main metabolite lovastatin acid in vivo. The pharmacodynamic results revealed that the Coptidis preparation and half-dose lovastatin group reduced the body weight, liver weight, and visceral fat in HFD rats. These findings provide constructive preclinical pharmacokinetic and pharmacodynamic applications of Coptidis preparation on the benefit of hyperlipidemia.

Figure 1

Chemical structures and mass spectra of (A) lovastatin, (B) lovastatin acid, and (C) nylidrin (internal standard; IS); molecular weights: 405, 423, and 300, respectively. The mass transitions of lovastatin, lovastatin acid, and nylidrin were m/z 405.4 → 285.3, 423.3 → 303.6, and 300.3 → 150.1, respectively.

Figure 2

Typical multiple reaction monitoring (MRM) chromatograms of (A) rat blank plasma and (B) lovastatin (10 ng/mL), lovastatin acid (100 ng/mL), and IS: nylidrin (1 ng/mL) spiked in rat plasma. (C) Rat plasma sample containing lovastatin (4.33 ng/mL) and lovastatin acid (87.07 ng/mL) collected 60 min after lovastatin oral administration (10 mg/kg). (1) IS: nylidrin (RT: 1.3 min), (2) lovastatin (RT: 3.6 min), and (3) lovastatin acid (RT: 3.6 min).

Figure 3

Concentration–time profiles of (A) lovastatin and (B) lovastatin acid in rat plasma following oral administration of 10 mg/kg lovastatin for the control group and the groups treated with dried decoctions of Coptidis preparation at 0.3, 1, and 3 g/kg. Data are expressed as the mean ± SD (n = 6).

Figure 4

Effects of lovastatin and Coptidis preparation on hepatic lipids in HFD-induced obese rats. Livers were stained with hematoxylin and eosin (H&E). Original magnification: 400× (scale bars, 100 μm). (A) HFD, (B) lovastatin (100 mg/kg), (C) Coptidis preparation (1 g/kg), and (D) lovastatin (50 mg/kg) and Coptidis preparation (1 g/kg).

Figure 5

Effects of lovastatin and Coptidis preparation on the epididymal fat size in HFD-induced obese rats. Epididymal fat tissues were stained with hematoxylin and eosin (H&E). Original magnification: 400× (scale bars, 100 μm). (A) ND group, (B) HFD group, (C) lovastatin 100 mg/kg group, (D) Coptidis preparation 1 g/kg group, and (E) epididymal fat in lovastatin 50 mg/kg and Coptidis preparation 1 g/kg group.

Figure 6

Effects of lovastatin and Coptidis preparation on the perirenal fat size in HFD-induced obese rats. Perirenal fat tissues were stained with hematoxylin and eosin (H&E). Original magnification: 400× (scale bars, 100 μm). (A) ND group, (B) HFD group, (C) lovastatin 100 mg/kg group, (D) Coptidis preparation 1 g/kg group, and (E) epididymal fat in lovastatin 50 mg/kg and Coptidis preparation 1 g/kg group.