Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers

Abstract

What is already known about this subject • Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia. • Danshen extract and theophylline may be prescribed together to treat patients with asthma. • In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2. • In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product. • There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). What this study adds • This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers. • Long‐term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline. • Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract. Aims To examine the potential effect of danshen extract on the pharmacokinetics of theophylline. Methods In a sequential cross‐over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h. Results The 90% confidence interval of Cmax, t1/2 and CL/F of theophylline with 14‐day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract. Conclusions Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets.

Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

“…However, our previous findings suggested that danshen extract tablet that contained lipophilic components had little effect on in vivo CYP1A2 activity in human. This might due to the low bioavailability of lipophilic components (Hao et al, 2006;Qiu et al, 2008). Since new pharmaceutical strategies such as micronization have been developed for promoting the absorption of tanshinone IIA into blood (Cai et al, 2006), further studies of in vivo drug-drug interactions between the novel danshen preparations and substrates of CYP1A2 remain necessary.…”

“…Ueng also reported that tanshinone IIA decreased 7-ethoxyresorufin O-deethylation and 7-methoxyresorufin O-demethylation activities in human liver microsomes (HLMs), suggesting that tanshinone IIA inhibited the activity of CYP1A2 in HLMs, and tanshinone IIA, tanshinone I, and cryptotanshinone inhibited the activity of cDNA-expressed CYP1A2 (Ueng et al, 2003). Our previous finding suggested that orally administered danshen extract had no significant effects on CYP1A2 in healthy volunteers (Qiu et al, 2008).…”

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

“…The main lipophilic components (cryptotanshinone, tanshinone I and tanshinone IIA) and hydrophilic components (danshensu, salvianolic acid B and protocatechuic aldehyde) of danshen tablets were separately determined by HPLC on a C18 column according to a previously published method [16]. For determination of hydrophilic components, elution with a mobile phase (0.5% acetic acid : methanol 80:20) was carried out at a flow rate of 1 ml min -1 .…”

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

“…The present in‐vivo results showed that Danshen aqueous extract inhibited CYP1A2 activity in the rat, as indicated by the paraxanthine / caffeine ratio and the plasma concentration–time profiles and pharmacokinetic parameters of caffeine. However, Qiu et al [12] . reported that Danshen extract tablets rich in hydrophilic components (salvianolic acid B and danshensu) did not affect the pharmacokinetics of theophylline (a probe substrate for evaluating CYP1A2 activity) in healthy volunteers.…”

“…Previous in‐vitro studies have shown that tanshinones (tanshinone I, tanshinone IIA, dihydrotanshinone and cryptotanshinone) isolated from Danshen may play an important role in the induction or inhibition of CYP1A2 in mice and humans [7–11] . On the other hand, a Danshen extract rich in hydrophilic components (salvianolic acid B and danshensu) did not affect the pharmacokinetics of theophylline in healthy volunteers and sodium tanshinone IIA sulfonate, a derivative of tanshinone IIA, induced the activity of CYP1A2 in healthy volunteers [12,13] . The different results and potential mechanisms require further exploration.…”