Effects of the aqueous extract from Salvia miltiorrhiza Bunge on caffeine pharmacokinetics and liver microsomal CYP1A2 activity in humans and rats

Objectives The effects of the aqueous extract of Salvia miltiorrhiza Bunge (Danshen) on metabolism/pharmacokinetics of caffeine and on liver microsomal CYP1A2 activity in humans and rats have been investigated. Methods The effects of Danshen aqueous extract on CYP1A2 activity were determined by metabolism of model substrates in the rat in vivo and in humans and rats in vitro. HPLC was used to determine model substrates and metabolites. Key findings In the rat, single dose Danshen aqueous extract treatment (100 or 200 mg/kg, i.p.) decreased metabolism of caffeine to paraxanthine, with overall decrease in caffeine clearance (6-20%), increase in area under the curve (AUC; 7-24%) and plasma half-life (t1/2 14-16%). Fourteen-day Danshen aqueous extract treatment (100 mg/kg/day, i.p. or 200 mg/kg/day, p.o.) decreased caffeine clearance (16-26%), increased AUC (18-31%) and prolonged plasma t1/2(8-10%). Aqueous extract of Danshen (125-2000 μg/ml) competitively inhibited human and rat liver microsomal CYP1A2 activity with inhibition constant (K_i) values at 190 and 360 μg/ml, respectively. Conclusions These studies demonstrated that Danshen aqueous extract affected the metabolism of CYP1A2 substrates through competitive inhibition and altered their clearance.