To　investigate　the　effects　of　P.　ginseng　C.A.　Mey　(P.　ginseng)　on　the　metabolism　of　diester　alkaloids　and　explore　the　potential　mechanism.　P.　ginseng　was　administered　orally　to　rats　for　7　days,　after　which　liver　microsome　samples　were　prepared　and　then　incubated　with　diester　alkaloids.　Ultra-high　performance　liquid　chromatography-quadrupole　time-of-flight　mass　spectrometry　was　used　to　determinate　the　concentration　of　diester　alkaloids　to　calculate　the　clearance　rate.　The　cocktail　method　was　used　to　evaluate　the　effects　of　oral　administration　of　P.　ginseng　extracts　on　the　activities　of　cytochrome　P450　(CYP)　isoforms　in　rats　through　the　changes　in　the　pharmacokinetic　parameters　of　the　probe　drugs.　The　protein　and　gene　expression　of　CYP3A2　and　pregnane　X　receptor　(PXR)　in　rats　were　evaluated　by　western　blotting　and　quantitative　PCR.　The　specific　enzyme　inhibitor　method　and　human　recombinant　enzyme　method　were　used　to　identify　the　involvement　of　sub-CYPs　in　the　metabolism　of　diester　alkaloids　in　human　liver　microsomes　(HLMs).　The　clearances　of　aconitine,　mesaconitine,　and　hypaconitine　in　the　P.　ginseng　groups　were　lower　than　those　of　the　control　group.　The　areas　under　the　curve　of　midazolam　were　2.37　+/-　1.05,　4.96　+/-　0.51,　and　6.23　+/-　1.30　mg.L-1.h　for　the　low-,　medium-,　and　high-dose　P.　ginseng　groups,　respectively,　which　were　higher　than　that　of　the　control　(2.23　+/-　0.64　mg.L-1.h).　The　clearances　of　midazolam　for　the　medium-　(1.87　+/-　0.16　L.h(-1).kg(-1))　and　high-dose　(1.60　+/-　0.34　L.h(-1).kg(-1))　P.　ginseng　groups　were　lower　than　that　of　the　control　group　(4.66　+/-　1.43　L.h(-1).kg(-1)).　After　exposure　to　P.　ginseng　extracts,　the　gene　and　protein　expression　levels　of　CYP3A4　and　PXR　were　decreased.　The　hepatic　metabolism　rates　of　aconitine,　mesaconitine,　and　hypaconitine　in　HLMs　were　decreased　to　60.37%,　21.67%,　and　10.11%,　respectively,　when　incubated　with　ketoconazole,　a　specific　inhibitor　for　CYP3A.　The　kinetic　plots　indicated　that　the　K-M　and　V-max　values　of　CYP3A4　were　10.08　+/-　3.26　mu　M　and　0.12　+/-　0.01nmol.mg　protein(-1).min(-1)　for　aconitine,　131.3　+/-　99.75　mu　M　and　0.73　+/-　0.44　nmol.mg　protein(-1).min(-1)　for　mesaconitine,　and　17.05　+/-　9.70　mu　M　and　0.16　+/-　0.04　nmol.mg　protein(-1).min(-1)　for　hypaconitine,　respectively.　The　in　vitro　mean　intrinsic　clearance　rates　by　CYP3A4　were　0.0119,　0.0056,　and　0.0091　mL.nmol　CYP-1.min(-1)　for　aconitine,　mesaconitine,　and　hypaconitine,　respectively.　Therefore　we　implied　that　P.　ginseng　inhibited　the　metabolism　of　diester　alkaloids　in　vitro　and　decreased　the　CYP3A4　enzyme　activity　as　well　as　the　gene　and　protein　expression　of　CYP3A4　and　PXR　in　vivo.　CYP3A4　had　a　larger　effect　on　diester　alkaloid　metabolism　than　the　other　human　CYP　isoforms,　CYP1A2,　CYP2C9,　and　CYP2E1.