***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The effects of goldenseal ( Hydrastis canadensis ) and kava kava ( Piper methysticum ) supplementation on human CYP3A activity were evaluated using midazolam ( MDZ ) as a phenotypic probe . Sixteen healthy volunteers were r and omly assigned to receive either goldenseal or kava kava for 14 days . Each supplementation phase was followed by a 30‐day washout period . MDZ ( 8 mg , per os ) was administered before and after each phase , and pharmacokinetic parameters were determined using st and ard non‐compartmental methods . Comparisons of pre‐ and post‐supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A  by goldenseal ( AUC(0–∞ ) , 107.9±43.3 vs 175.3±74.8 ng·h/ml ; Cl/F/kg , 1.26±0.59 vs 0.81±0.45 l/h/kg ; T1/2 , 2.01±0.42 vs 3.15±1.12 h ; Cmax , 50.6±26.9 vs 71.2±50.5 ng/ml ) . MDZ  disposition was not affected by kava kava supplementation . These findings suggest that significant herb – drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates Phytochemical‐mediated modulation of cytochrome P450 ( CYP ) activity may underlie many herb‐drug interactions . Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of Citrus aurantium , Echinacea purpurea , milk thistle ( Silybum marianum ) , or saw palmetto ( Serenoa repens ) extracts affected CYP1A2 , CYP2D6 , CYP2E1 , or CYP3A4 activity Phytochemical-mediated modulation of P-glycoprotein ( P-gp ) and other drug transporters may give rise to many herb-drug interactions . Serial plasma concentration-time profiles of the P-gp substrate , digoxin , were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo . Twenty healthy volunteers were r and omly assigned to receive a st and ardized goldenseal ( 3210 mg daily ) or kava kava ( 1227 mg daily ) supplement for 14 days , followed by a 30-day washout period . Subjects were also r and omized to receive rifampin ( 600 mg daily , 7 days ) and clarithromycin ( 1000 mg daily , 7 days ) as positive controls for P-gp induction and inhibition , respectively . Digoxin ( Lanoxin , 0.5 mg ) was administered p.o . before and at the end of each supplementation and control period . Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay . Comparisons of area under the curve (AUC)(0–3 ) , AUC(0–24 ) , Cmax , CL/F , and elimination half-life were used to assess the effects of goldenseal , kava kava , rifampin , and clarithromycin on  digoxin pharmacokinetics .  Rifampin produced significant reductions ( p < 0.01 ) in AUC(0–3 ) , AUC(0–24 ) , CL/F , t1/2 , and Cmax , whereas clarithromycin increased these parameters significantly ( p < 0.01 ) . With the exception of goldenseal 's effect on Cmax ( 14 % increase ) , no statistically significant effects on  digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava . When compared with rifampin and clarithromycin , supplementation with these specific formulations of goldenseal or kava kava did not appear to affect  digoxin pharmacokinetics , suggesting that these supplements are not potent modulators of P-gp in vivo The effects of berberine ( BBR ) on the pharmacokinetics of ciclosporin A ( CsA ) were examined in healthy volunteers . Six healthy male volunteers were orally treated with 0.3 g BBR , twice daily for 10 days . Pharmacokinetic investigations on CsA at 6 mg/kg were done both before and at the end of the BBR treatment period . Another six healthy male volunteers were involved in the pharmacokinetic study with 3 mg CsA/kg  , in which the subjects orally received the second single dose of 3 mg CsA/kg , followed by a single oral dose of 0.3 g BBR . The blood CsA concentrations were determined by fluorescence polarization immunoassay . In the pharmacokinetic study with 6 mg CsA/kg , BBR caused no significant changes in the pharmacokinetic parameters of CsA. However , in the trial with 3 mg CsA/kg , the average percentage increase in area under the blood concentration-time curve of CsA was 19.2 % ( P < 0.05 ) and the mean C12 increased to 123 microg/l from 104 microg/l ( P < 0.05 ) , without altering elimination half-life ( t(1/2 ) ) , maximum blood drug concentration ( Cmax ) , time to Cmax ( tmax ) , apparent oral clearance ( CL/F ) . The present results suggest that BBR can increase the oral bioavailability of CsA at the dosage of 3 mg/kg . The BBR-mediated increase in CsA bioavailability may be partly attributed to a decrease in liver and /or intestinal metabolism through the inhibition of CYP3A4 in the liver and /or gut wall . The BBR-induced increase in emptying time of stomach and small intestine might be another reason for the increase in CsA bioavailability . However , the speculation should be proved by further investigation Phytochemical-mediated modulation of P-glycoprotein ( P-gp ) and other drug transporters may underlie many herb-drug interactions . Serial serum concentration-time profiles of the P-gp substrate , digoxin , were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo . Sixteen healthy volunteers were r and omly assigned to receive a st and ardized milk thistle ( 900 mg daily ) or black cohosh ( 40 mg daily ) supplement for 14 days , followed by a 30-day washout period . Subjects were also r and omized to receive rifampin ( 600 mg daily , 7 days ) and clarithromycin ( 1000 mg daily , 7 days ) as positive controls for P-gp induction and inhibition , respectively . Digoxin ( Lanoxicaps , 0.4 mg ) was administered orally before and at the end of each supplementation and control period . Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay . Comparisons of area under the serum concentration time curves from 0 to 3 h ( AUC(0–3 ) ) , AUC(0–24 ) , Cmax , apparent oral clearance of digoxin ( CL/F ) , and elimination half-life were used to assess the effects of milk thistle , black cohosh , rifampin , and clarithromycin on digoxin pharmacokinetics . Rifampin produced significant reductions ( p < 0.01 ) in AUC(0–3 ) , AUC(0–24 ) , and Cmax , whereas clarithromycin increased these parameters significantly ( p < 0.01 ) . Significant changes in digoxin half-life and CL/F were also observed with clarithromycin . No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh , although digoxin AUC(0–3 ) and AUC(0–24 ) approached significance ( p = 0.06 ) following milk thistle administration . When compared with rifampin and clarithromycin , supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics , suggesting that these supplements are not potent modulators of P-gp in vivo Phytochemical‐mediated modulation of cytochrome P450 ( CYP ) activity may underlie many herb‐drug interactions . Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of goldenseal ( Hydrastis canadensis ) , black cohosh ( Cimicifuga racemosa ) , kava kava ( Piper methysticum ) , or valerian ( Valeriana officinalis ) extracts affected CYP1A2 , CYP2D6 , CYP2E1 , or CYP3A4/5 activity Purpose We assessed the human in vivo metabolic drug interaction profile of Ginkgo biloba extract EGb 761 ® with respect to the activities of major cytochrome P450 ( CYP ) enzymes . Methods A single-center , open-label , r and omized , three-fold crossover , cocktail phenotyping design was applied . In r and om order , the following treatments were administered to 18 healthy men and women for 8 days each : placebo twice daily , EGb 761 ® 120 mg twice daily , and EGb 761 ® 240 mg in the morning and placebo in the evening . In the morning of day 8 , administration was performed together with the orally administered phenotyping cocktail ( enzyme , metric ) : 150 mg caffeine ( CYP1A2 , paraxanthine/caffeine plasma ratio 6-h postdose ) , 125 mg tolbutamide ( CYP2C9 , plasma concentration 24-h postdose ) , 20 mg omeprazole ( CYP2C19 , omeprazole/5-hydroxy omeprazole plasma ratio 3-h postdose ) , 30 mg dextromethorphan ( CYP2D6 , dextromethorphan/dextrorphan plasma ratio 3-h postdose ) , and 2 mg of midazolam ( CYP3A , plasma concentration 6-h postdose ) . Formally , absence of a relevant interaction was assumed if the 90 % confidence intervals ( CIs ) for EGb 761 ® /placebo ratios of the metrics were within the 0.70–1.43 range . Results EGb 761 ® /placebo ratios for phenotyping metrics were close to unity for all CYPs . Furthermore , respective CIs were within the specified margins for all ratios except CYP2C19 for EGb 761 ® 120 mg twice daily ( 90 % CI 0.681–1.122 ) and for CYP2D6 for EGb 761 ® 240 mg once daily ( 90 % CI 0.667–1.281 ) . These findings were attributed to the intraindividual variability of the metrics used . All treatments were well tolerated . Conclusion EGb 761 ® has no relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no relevant potential to cause respective metabolic drug – drug interactions BACKGROUND & AIMS Ginkgo biloba extract ( EGb 761 ) has been shown to ameliorate some defects associated with the insulin resistance syndrome and so patients with Type 2 diabetes mellitus ( T2DM ) may be inclined to co-ingest the herb with their medications , such as metformin . This study was design ed to determine if the co-ingestion of EGb 761 and metformin would alter the pharmacokinetic properties of  metformin in T2DM patients and persons without diabetes , who may ingest it for other purpose s. METHOD Normal glucose tolerance ( NGT ) subjects ( n=10 ; age , 39.2+/-14.0 years ; fasting plasma glucose ( FPG ) , 90+/-7 mg/dl ; body mass index ( BMI ) , 24.1+/-3.7 kg/m(2 ) ) and 10 T2DM patients ( n=10 ; age , 51.7+/-8.9 years ; FPG , 150+/-7 mg/dl ; BMI , 33.7+/-5.7 kg/m(2 ) ) completed a r and omized , double-blind , placebo-controlled crossover study . They ingested either EGb 761 ( 12 0mg/day as a single dose ) or a vegetable-based placebo during each arm for 3 months . At the end of each arm , the NGT subject ingested a single 500 mg dose of metformin ( non-diabetics ) and the T2DM subject took his/her prescribed metformin dose ( 250 - 850 mg ) with 120 mg EGb 761 . Blood and urine sample s were collected over an 8-h period , and in the case of T2DM subjects , additionally over the first 2h of the subsequent 3 days . RESULTS Ingestion of EGb 761 produced no significant changes in diagnostic laboratory tests in either group , except reducing glycosylated hemoglobin A(1c ) levels ( from 7.7+/-1.2 to 7.2+/-0.9 % , P<0.05 ) in T2DM the 
    Output:
    
Collectively , the available evidence indicates that , at commonly recommended doses , none of these herbs act as potent or moderate inhibitors or inducers of cytochrome P450 ( CYP ) enzymes or P-glycoprotein ( ABCB1 ) .
Weak effects in terms of either induction or inhibition were found for GB ( presystemic/hepatic CYP3A4 induction/inhibition , CYP2C19 induction at high doses ) , milk thistle/silymarin ( CYP2C9 inhibition ) , GS/berberine ( CYP3A4 and CYP2D6 inhibition ) , Echinacea ( presystemic/hepatic CYP3A4 inhibition/induction , CYP1A2 and CYP2C9 inhibition at high doses ) .
Information was found not always complete for the major drug metabolizing CYP enzymes in the less well-studied herbs and is largely limited to P-glycoprotein ( ABCB1 ) when effects on drug transporters have been investigated