In vivo distribution and pharmacokinetics of multiple active components from Danshen and Sanqi and their combination via inner ear administration

Abstract

Ethnopharmacological relevance: Salvia miltiorrhiza Bunge (Labiatae sp. plant, Chinese name Danshen) and Panax notoginseng (Burk.) F. H. Chen (Araliaceae plant, Chinese name Sanqi) have a long history in treating coronary heart disease, cerebrovascular disease and inner ear disorders in traditional Chinese medicine. To provide a rational basis for the use of these herbs in clinical practice, we investigated the in vivo distribution and pharmacokinetics of marker agents in Danshen and Sanqi via intravenous and inner ear administration and explored the potential interactions of these agents in compound prescription.

Materials and methods: Guinea pigs were given Danshen extracts (salvianolic acid B, tanshinone IIA), Sanqi extracts (Panax notoginseng saponins) and combination of the two extracts via intravenous and intratympanic administration (IT). Samples from the brain, inner ear perilymph (PL), cerebrospinal fluid (CSF) and plasma were collected at different time points. The concentration of salvianolic acid B (Sal B), tanshinone IIA (Ts IIA), notoginsenoside R₁ (R₁), ginsenoside Rg₁ (Rg₁) and ginsenoside Rb₁ (Rb₁) was determined by high-performance liquid chromatography coupled with a diode array detector (DAD). Pharmacokinetic parameters were estimated using non-compartmental methods.

Results: Local drug application via inner ear greatly improved drug distribution within the PL, CSF and brain tissues compared with intravenous administration (IV). The values of Cmax and AUC(0-t) after IT were significantly higher than IV. In comparison with IT of Danshen and Sanqi alone, the pharmacokinetic parameters for R₁, Rg₁, Rb₁, Sal B and Ts IIA were markedly different in the compound prescription. The compound compatibility enhanced the transport of Danshen components into the brain through the inner ear and apparently prolonged the retention time in CSF while decreasing the distribution of Sanqi components in the inner ear and brain.

Conclusions: The results indicated that local drug application to the inner ear was a more effective delivery route than systemic administration. Co-administration of Danshen and Sanqi could cause significant pharmacokinetic herb-herb interactions in guinea pigs. The multiple active components via inner ear administration might be promising candidates for the treatment of inner ear and brain diseases.

Keywords: Danshen; Ginsenoside Rb(1) (PubChem CID: 9898279); Ginsenoside Rg(1) (PubChem CID: 441923); In vivo distribution; Inner ear administration; Notoginsenoside R(1) (PubChem CID: 441934); Pharmacokinetics; Salvianolic acid B (PubChem CID: 11629084); Sanqi; Tanshinone IIA (PubChem CID: 164676).