***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: Milk thistle ( Silybum marianum ) extracts are widely used as a complementary and alternative treatment of various hepatic conditions and a host of other diseases/disorders . The active constituents of milk thistle supplements are believed to be the flavonolignans contained within the extracts . In vitro studies have suggested that some milk thistle components may significantly inhibit specific cytochrome P450 ( P450 ) enzymes . However , determining the potential for clinical ly significant drug interactions with milk thistle products has been complicated by inconsistencies between in vitro and in vivo study results . The aim of the present study was to determine the effect of a st and ardized milk thistle supplement on major P450 drug-metabolizing enzymes after a 14-day exposure period . CYP1A2 , CYP2C9 , CYP2D6 , and CYP3A4/5 activities were measured by simultaneously administering the four probe drugs , caffeine , tolbutamide , dextromethorphan , and midazolam , to nine healthy volunteers before and after exposure to a st and ardized milk thistle extract given thrice daily for 14 days . The three most abundant falvonolignans found in plasma , following exposure to milk thistle extracts , were silybin A , silybin B , and isosilybin B. The concentrations of these three major constituents were individually measured in study subjects as potential perpetrators . The peak concentrations and areas under the time-concentration curves of the four probe drugs were determined with the milk thistle administration . Exposure to milk thistle extract produced no significant influence on CYP1A2 , CYP2C9 , CYP2D6 , or CYP3A4/5 activities Objectives : Since grapefruit juice ( Gra ) inhibits hepatic P450 ( CYP3A4 ) , we studied its potential to enhance the effects of midazolam ( Mid ) and triazolam ( Trz ) , which are metabolized by the CYP3A4 isoenzyme . Methods : In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice ( GraMid ) , two placebo groups receiving water or Gra . The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue scales before and 30 and 90 min after intake . Study II was similar , but the post-treatment tests were at 45 and 90 min , and the active drugs used were 0.250 mg Trz , GraTrz , and Mid 10 mg . In the crossover Study III , 6 subjects took Mid 10 mg alone and with Gra ( GraMid ) and 750 mg erythromycin ( EryMid ) . Performance tests were made and blood was sample d before and 30 , 60 and 90 min after intake . Midazolam and its active metabolite α-OH-midazolam were assayed by gas chromatography ( GC ) and radioreceptor assay ( RRA ) . Results : In Study I , both Mid and GraMid impaired digit symbol substitution ( DSS ) , letter cancellation ( LC ) and flicker fusion ( CFF ) at 90 min . GraMid had more effect ( P < 0.05 ) than Mid on the DSS performance . Mid caused drowsiness at 30 and 90 min . Both Mid and GraMid caused clumsiness and a feeling of impaired performance at 90 min . In Study II , the active drugs impaired objective test performances ( DSS , LC , CFF ) at 90 min , without having a clear subjective effect . In Study III , Mid , EryMid and GraMid impaired performance in the DSS , LC and CFF tests . EryMid proved stronger than Mid and GraMid on DSS and LC tests at 30 min . Mean values of plasma midazolam ( and α-OH-midazolam ) at 30 , 60 , 90 and 120 min after Mid 10 mg were 68 ( 19 ) , 61 ( 19 ) , 43 ( 14 ) and 42 ( 12 ) μg⋅l−1 . The corresponding values after EryMid were 164 ( 14 ) , 137 ( 13 ) , 104(10 ) and 89(10 ) μg ⋅l−1 , and after GraMid 60 ( 12 ) , 69 ( 16 ) , 61 ( 15 ) and 57 ( 14 ) μg⋅l−1 . Conclusions : The grapefruit juice used did have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects BACKGROUND Grapefruit juice ( GFJ ) enhances the systemic exposure of numerous CYP3A4 drug substrates , including felodipine , by inhibiting intestinal ( but not hepatic ) first-pass metabolism . Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice , but their contribution to the GFJ effect in vivo remains unclear . OBJECTIVE To ascertain whether furanocoumarins mediate the  GFJ-felodipine  interaction , a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine . DESIGN With the use of food- grade solvents and absorption resins , furanocoumarins were removed ( approximately 99 % ) from whole GFJ , whereas other major ingredients ( flavonoids ) were retained . In an open , 3-way , r and omized crossover design , 18 healthy volunteers ingested felodipine ( 10 mg ) with 1 of the 3 juices ( 240 mL ) . Blood was collected over 24 h. At least 1 wk elapsed between juice treatments . RESULTS The median and range of the area under the curve and the maximum concentration of felodipine were significantly ( P < 0.001 ) greater with consumption of GFJ [ 110 ( range : 58 - 270 ) nmol . h/L and 21 ( 7.6 - 50 ) nmol/L , respectively ] than with that of orange juice [ 54 ( 29 - 150 ) nmol . h/L and 7.6 ( 3.4 - 13.9 ) nmol/L , respectively ] or furanocoumarin-free GFJ [ 48 ( 23 - 120 ) nmol . h/L and 8.3 ( 3.0 - 16.6 ) nmol/L , respectively ] . GFJ , orange juice , and furanocoumarin-free GFJ did not differ significantly ( P > 0.09 ) in median time to reach maximum plasma concentration [ 2.5 ( 1.5 - 6 ) , 2.8 ( 1.5 - 4 ) , and 2.5 ( 2 - 6 ) h , respectively ] or terminal half-life [ 6.6 ( 4.2 - 13.6 ) , 7.8 ( 4.4 - 13.2 ) , and 6.8 ( 2.6 - 14.4 ) h , respectively ] . CONCLUSION Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism Systemic clearance of intravenous ( IV ) alfentanil ( ALF ) is an in vivo probe for hepatic cytochrome P450 ( CYP ) 3A activity , miosis is a surrogate for plasma ALF concentrations , and IV ALF miosis is a noninvasive probe for hepatic CYP3A . This investigation characterized the bioavailability and first‐pass metabolism of oral ALF and tested the hypotheses that ( 1 ) first‐pass ALF clearance reflects first‐pass CYP3A activity , ( 2 ) miosis after oral ALF will reflect intestinal and hepatic CYP3A activity , and ( 3 ) miosis can approximate plasma concentration‐based pharmacokinetic measures for IV and oral ALF as a noninvasive in vivo probe for hepatic and first‐pass CYP3A activity and drug interactions . Results were compared with those for midazolam ( MDZ ) , an alternative CYP3A probe Consumption of typical quantities of grapefruit juice ( GFJ ) increases the oral bioavailability of several CYP3A4 substrates without affecting their elimination , consistent with selective inhibition of intestinal but not hepatic CYP3A4 . However , increases in the AUCs of CYP3A4 substrates recently associated with the consumption of large amounts of GFJ were similar to those observed with potent inhibitors of hepatic CYP3A4 . The current study compared the effects of consuming large quantities and more typical amounts of GFJ on the activity of hepatic and intestinal cytochrome P450 3A4 in vivo , employing the erythromycin breath test ( EBT ) and oral midazolam pharmacokinetics . This was a two-phase , r and omized , placebo-controlled crossover study , with each phase conducted with a separate panel of subjects . In Phase I , 8 male volunteers were r and omized to the order of receiving one glass ( 240 mL ) of water ( placebo ) or double-strength ( DS ) GFJ tid for 2 days and then 90 , 60 , and 30 minutes prior to administration of probe drugs on the 3rd day . In Phase II , 16 male volunteers were r and omized to the order of receiving one glass of ( 1 ) single-strength ( SS ) GFJ , ( 2 ) DS GFJ , and ( 3 ) water ( placebo ) . All treatments were administered in a fasted state . There was at least a 7-day washout period between treatments . Probe drugs , administered 30 minutes or 1 hour following each treatment in Phase I or II , respectively , consisted of oral midazolam ( 2 mg ) coadministered with IV [ 14 G N-methyl ] erythromycin ( 0.03 mg ) . The EBT was performed 20 minutes following erythromycin administration . Blood was collected during the 24 hours following probe drug administration for the analysis of midazolam pharmacokinetics . In Phase I , consumption of one glass of DS GFJ tid for 3 days increased the Cmax of midazolam 3-fold , the AUC 6-fold , and the t1/2 2-fold and decreased the amount of exhaled 14CO2 in all 8 subjects , with a mean decrease in EBT of 18 % . In Phase II , consumption of one glass of DS GFJ significantly increased the AUC and Cmax of midazolam approximately 2-fold without a significant effect on the t1/2 of midazolam or the EBT . The effects of consuming one glass of SS GFJ on midazolam pharmacokinetics and the EBT were not significantly different from those of one glass of DS GFJ . It was concluded that consumption of one glass of DS GFJ tid for 3 days significantly increased the AUC , Cmax , and t1/2 of midazolam and reduced EBT values , reflecting inhibition of both hepatic and intestinal CYP3A4 . In contrast , consumption of one glass of SS or DS GFJ increased midazolam AUC and Cmax , with little effect on the midazolam t1/2 and EBT values , reflecting preferential inhibition of intestinal CYP3A4 . Alterations of midazolam AUC and Cmax induced by nine glasses of DS GFJ were significantly greater than those produced by one glass of SS or DS GFJ . These data suggest that GFJ inhibits intestinal and hepatic CYP3A4 in an exposure-dependent fashion and that patients taking medications that are CYP3A4 substrates are at risk for developing drug-related adverse events if they consume large amounts of grapefruit juice To evaluate the effect of regular‐strength grapefruit juice , a cytochrome P4503A4 ( CYP3A4 ) inhibitor , on the pharmacokinetics of a commonly prescribed regimen of oral lovastatin Grapefruit juice produces a marked and variable increase in felodipine bioavailability . The pharmacokinetics of felodipine and its single primary oxidative metabolite , dehydrofelodipine , were studied after drug administration with 200 ml water , grapefruit juice , or naringin in water at the same concentration as the juice in a r and omized crossover trial of nine healthy men .  With grapefruit juice , mean ± SEM felodipine area under the plasma concentration‐time curve ( AUC ) and peak plasma concentration ( Cmax ) were 206 % ± 23 % ( range , 123 % to 330 % , p < 0.01 ) and 170 % ± 24 % ( range , 127 % to 310 % , p < 0.02 ) , respectively , compared with water . Dehydrofelodipine/felodipine ratios for AUC ( 1.5 ± 0.2 versus 2.2 ± 0.2 , p < 0.001 ) and felodipine Cmax ( 1.5 ± 0.2 versus 2.2 ± 0.2 , p < 0.001 ) were reduced , consistent with inhibition of presystemic felodipine 
    Output:
    
The current study indicated grapefruit juice‐drug interaction varies substantially based on patient characteristics and /or grapefruit juice product‐related factors , including the amount of furanocoumarin constituents present in the juice