Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

Figures & data

Figure 1. The chemical structure of losartan (A), irbesartan (B) and EXP3174 (C).

Figure 2. The mass spectra of losartan (A), EXP3174 (B) and irbesartan (C).

Figure 3. (A) Representative chromatograms of blank plasma; (B) blank plasma spiked with losartan (2), EXP3174 (3) and irbesartan (1); (C) rat plasma treated with BBR and losartan.

Table 1. The precision and accuracy of losartan and EXP3174 in plasma samples.

		Intra-day			Inter-day
Analyte	Plasma samples (ng/mL)	concentrationmeasured (ng/mL)	Precision(%, RSD)	Accuracy(%, RE)	concentrationmeasured (ng/mL)	Precision(%, RSD)	Accuracy(%, RE)
Losartan	20	18.58	6.42	−7.10	18.21	8.28	−8.95
	200	191.36	4.83	−4.32	212.49	7.51	6.25
	1000	1094.25	8.64	9.43	921.54	4.56	−7.85
EXP3174	50	46.35	6.46	−7.3	47.35	7.32	−5.30
	200	212.37	5.21	6.19	208.38	6.84	4.19
	2000	1885.25	9.64	−5.74	1894.42	6.72	−5.28

Table 2. Stability of losartan and EXP3174 in plasma samples (n = 3).

		Stability (%, RE)
Analyte	Plasma samples(ng/mL)	Short-term(4 h at room temperature)	Autosampler(24 h)	Three freeze–thawcycles at −40 °C	Long-term(15 days at −40 °C)
Losartan	20	8.13	6.51	5.24	−4.18
	200	−7.54	5.64	6.37	6.85
	1000	9.98	4.87	8.55	9.54
EXP3174	50	−6.87	7.35	6.19	8.30
	200	5.58	6.84	−4.35	5.25
	2000	6.49	−5.52	7.37	6.87

Figure 4. The mean concentration–time curves in rat plasma after oral administration of single losartan and both losartan and BBR, (A) losartan and (B) EXP3174.

Table 3. Pharmacokinetic parameters of losartan and EXP3174 in male Sprague-Dawley rats following oral administration of losartan alone and both losartan and BBR.

	Losartan		EXP3174
Parameter	Group A	Group B	Group A	Group B
Tmax (h)	0.41 ± 0.12	0.52 ± 0.18	8.14 ± 0.36	3.33 ± 0.28*
Cmax (mg/L)	1.26 ± 0.37	1.96 ± 0.45*	0.97 ± 0.15	0.77 ± 0.06*
t1/2 (h)	5.54 ± 1.15	5.58 ± 1.36	4.53 ± 0.44	4.99 ± 0.51
AUC(0–t) (mg h/L)	8.25 ± 0.89	12.70 ± 1.42*	11.87 ± 2.31	9.36 ± 1.94*
AUMC(0–t) (mg h/L)	47.58 ± 7.63	80.93 ± 14.64*	100.29 ± 18.36	72.89 ± 17.19*
CL (L/h kg)	2.27 ± 0.38	1.51 ± 0.28*	1.65 ± 0.28	2.10 ± 0.42
MRT (h)	5.79 ± 0.47	6.30 ± 0.87	8.44 ± 0.68	7.76 ± 0.57

* p < 0.05 indicates significant differences from the control.

Figure 5. (A) Representative chromatograms of blank microsome incubation solutions; (B) blank microsome incubation solution spiked with losartan (2), EXP3174 (3) and irbesartan (1); (C) blank microsome incubation solution treated with BBR and losartan.