***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: 3-Hydroxy-3-methylglutaryl-coenzyme A ( HMG-CoA ) reductase inhibitors are often prescribed in association with antihypertensive agents , including calcium antagonists . Simvastatin is an HMG-CoA reductase inhibitor that is metabolized by the cytochrome P450 ( CYP ) 3A4 . The calcium antagonist amlodipine is also metabolized by CYP3A4 . The purpose of this study was to investigate drug interactions between amlodipine and simvastatin .  Eight patients with hypercholesterolemia and hypertension were enrolled . They were given 4 weeks of oral simvastatin ( 5 mg/day ) , followed by 4 weeks of oral amlodipine ( 5 mg/day ) co-administered with simvastatin ( 5 mg/day ) . Combined treatment with simvastatin and amlodipine increased the peak concentration ( Cmax ) of HMG-CoA reductase inhibitors from 9.6 ±3.7 ng/ml to 13.7±4.7 ng/ml ( p<0.05 ) and the area under the concentration-time curve ( AUC ) from 34.3±16.5 ng h/ml to 43.9±16.6 ng h/ml ( p<0.05 ) without affecting the cholesterol-lowering effect of simvastatin . This study is the first to determine prospect ively the pharmacokinetic and pharmacodynamic interaction between amlodipine and simvastatin Purpose To characterise further the previously observed cytochrome P450 3A4 ( CYP3A4 ) interaction of the dual orexin receptor antagonist almorexant . Methods Pharmacokinetic interactions were investigated ( n = 14 healthy male subjects in two treatment groups ) between almorexant at steady-state when administered either concomitantly or 2 h after administration of single doses of simvastatin ( 40 mg ) or atorvastatin ( 40 mg ) . Results Almorexant dose-dependently increased simvastatin exposure ( AUC0–∞ ) when administered concomitantly [ geometric mean ratios ( 90 % CI ) : 2.5 ( 2.1 , 2.9 ) ( 100 mg ) , 3.9 ( 3.3 , 4.6 ) ( 200 mg ) ] , but not Cmax [ 3.7 ( 3.0 , 4.5 ) for both doses ] . Time-separated administration result ed in relevant reductions of the interaction [ AUC0–∞ : 1.4 ( 1.2 , 1.7 ) ( 100 mg ) , 1.7 ( 1.5 , 2.0 ) ( 200 mg ) ; Cmax : 1.5 ( 1.3 , 1.9 ) ( 100 mg ) , 1.9 ( 1.6 , 2.4 ) ( 200 mg ) ] . Similar results were obtained for hydroxyacid simvastatin . Independent of almorexant dose and relative time of administration , AUC0–∞ and Cmax of atorvastatin increased ( ratios ranged from 1.1 to 1.5 ) . AUC0–∞ and Cmax of o-hydroxy atorvastatin decreased dose-independently [ AUC0–∞ : 0.8 ( 0.8 , 0.9 ) ( 100 mg ) , 0.6 ( 0.5 , 0.6 ) ( 200 mg ) ; Cmax : 0.3 ( 0.3 , 0.4 ) ( 100 mg ) , 0.2 ( 0.2 , 0.3 ) ( 200 mg ) ] when atorvastatin was concomitantly administered . Cmax of o-hydroxy atorvastatin slightly decreased ( 0.8 for both doses ) following time-separated administration ; AUC0–∞ was unchanged . Conclusions Whereas almorexant increased simvastatin exposure dose- and relative time of administration-dependently , atorvastatin exposure increased to a smaller extent and irrespective of dose and time . This suggests that the observed interaction of almorexant with simvastatin is mainly caused by intestinal CYP3A4 inhibition , whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition Three-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors ( statins ) are first-line treatments for hypercholesterolemia . Although exceedingly well tolerated , treatment with statins incurs a small risk of myopathy or potentially fatal rhabdomyolysis , particularly when coadministered with medications that increase their systemic exposure . Studies compared the multiple-dose pharmacokinetic interaction profiles of pravastatin , simvastatin , and atorvastatin when coadministered with 4 inhibitors of cytochrome P450 - 3A4 isoenzymes in healthy subjects . Compared with pravastatin alone , coadministration of verapamil , mibefradil , or itraconazole with pravastatin was associated with no significant changes in pravastatin pharmacokinetics . However , concomitant verapamil increased the simvastatin area under the concentration : time curve ( AUC ) approximately fourfold , the maximum serum concentration ( C(max ) ) fivefold , and the active metabolite simvastatin acid AUC and C(max ) approximately four- and threefold , respectively ( all comparisons p < 0.001 ) . Similar ( greater than fourfold ) important increases in these parameters and a > 60 % increase in the serum half-life ( p = 0.03 ) of atorvastatin were observed when coadministered with mibefradil . The half-life of atorvastatin also increased by approximately 60 % ( p = 0.052 ) when coadministered with itraconazole , which elicited a 2.4-fold increase in the C(max ) of atorvastatin and a 47 % increase in the AUC ( p < 0.001 for C(max ) and AUC ) . Clarithromycin significantly ( p < 0.001 ) increased the AUC ( and C(max ) ) of all 3 statins , most markedly simvastatin ( approximately 10-fold increase in AUC ) and simvastatin acid ( 12-fold ) , followed by atorvastatin ( greater than fourfold ) and then pravastatin ( almost twofold ) . Pravastatin has a neutral drug interaction profile relative to cytochrome P450 - 3A4 inhibitors , but these substrates markedly increase systemic exposure to simvastatin and atorvastatin The objective of this study was to evaluate the effect of the CYP3A5 * 3 allele on the pharmacokinetics of tacrolimus and amlodipine  , and drug-drug interactions between them in healthy subjects .  Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a r and omized , 3-period , 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype . A single-dose and multiple-dose study were design ed . A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose , and the washout periods between the study phases were 14 days . In the single-dose study , apparent oral clearance ( CL/F ) of  tacrolimus  ( 5 mg ) in CYP3A5 expressers was 3.8-fold ( p = 0.008 ) higher than that in CYP3A5 non-expressers . Amlodipine  decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold ( p = 0.005 ) , while it had no effect on that in CYP3A5 non-expressers . The CL/F of amlodipine  in CYP3A5 non-expressers was 2.0-fold ( p = 0.001 ) higher than that in CYP3A5 expressers .  Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold ( p = 0.016 ) while it had no effect on that in CYP3A5 non-expressers . Tacrolimus slightly reduced the AUC₀-∞ of amlodipine  in both CYP3A5 expressers and non-expressers . Dose adjustment of tacrolimus should be considered according to CYP3A5 * 3 genetic polymorphism when tacrolimus is coadministered with amlodipine AIMS Lacidipine , a long acting 2 , 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents , particularly in elderly population s. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated , since they share the CYP3A4 pathway for metabolism . METHODS The study was an open , r and omised , two-way crossover design , with at least 7 days washout . Eighteen healthy subjects received simvastatin , 40 mg once daily , alone and together with lacidipine , 4 mg once daily , for 8 days . The pharmacokinetics of simvastatin were studied on the eighth day . Analysis was made of total simvastatin acid concentrations ( naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone ) . RESULTS Lacidipine increased the maximum concentration of simvastatin ( Cmax ) by approximately 70 % ( P=0.016 ) and the area under the plasma concentration-time curve AUC(0,24 h ) by approximately 35 % ( P=0.001 ) . The mean Cmax and AUC(0,24 h ) of simvastatin ( 95 % confidence interval ) when given alone were 8.76 ( 6.72 - 11.41 ) ng ml(-1 ) and 60.36 ( 47.15 - 77.28 ) ng ml(-1 ) h. During treatment with lacidipine they were , respectively , 14.89 ( 10.77 - 20.58 ) ng ml(-1 ) and 80.96 ( 64.62 - 101.44 ) ng ml(-1 ) h. No significant differences were observed in either time to peak concentration ( tmax was 1.0 h for simvastatin alone and 1.5 h for the combination ) or in the half-life ( t1/2,z was 8.5 h in both cases ) . The combination was safe and well tolerated . CONCLUSIONS The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance OBJECTIVES To explore if non-concurrent amlodipine dosing results in less drug interaction , the pharmacokinetic profiles , safety and efficacy endpoints were assessed following repeated doses of simvastatin , co-administered concurrently or non-concurrently with amlodipine in patients with coexisting hypertension and hyperlipidemia . METHODS Seventeen patients r and omly received daily doses of 20 mg simvastatin and 5 mg amlodipine for 6 weeks , either with both drugs at 7:00 PM ( concurrent ) or with simvastatin at 7:00 PM followed by amlodipine at 11:00 PM ( non-concurrent ) . The maximum plasma concentration ( Cmax ) and the area under the concentration-time curve up to the last quantifiable concentration ( AUClast ) were estimated at steady state . Lipid profiles and blood pressure values were also compared between the concurrent and non-concurrent groups . RESULTS The Cmax and AUClast and of simvastatin acid in the non-concurrent amlodipine dosing group were 63.2 % and 66.0 % , respectively , of the values obtained in the concurrent group ( 1.2 + /- 1.0 vs. 1.9 + /- 0.9 ng/ml and 10.3 + /- 8.3 vs. 15.6 + /- 7.5 h ng/ml , respectively , mean + /- st and ard deviation ) . Changes from baseline in lipid profile and blood pressure were comparable between the groups . CONCLUSIONS Non-concurrent dosing may be a useful and safe therapeutic option for patients who require two or more drugs administered concomitantly , but who are likely to develop unwanted drug interactions A r and omized cross-over pharmacokinetic study of rosuvastatin calcium ( single dose : 5 mg , 10 mg and 20 mg ; multiple doses : 10 mg once daily for 7 days ) was conducted in 12 healthy Chinese volunteers . Plasma concentrations of rosuvastatin were determined by an LC-ESI-MS-MS method . Single-nucleotide polymorphisms ( SNPs ) in ABCB1 , ABCG2 , SLCOB1 , CYP2C9 and CYP3A5 were determined by TaqMan ( MGB ) genotyping assay . An impact of the aforementioned SNPs on steady state pharmacokinetic parameters [ average steady state concentration ( Cav , ss ) and area under the plasma concentration versus time curve during the dosing interval at steady state ( AUCss ) ] , dose-normalized ( based on 5 mg ) pharmacokinetic parameters of single-dose rosuvastatin were further analyzed . Rosuvastatin exhibited linear pharmacokinetics and great inter-subject variability . Cav , ss , AUCss and dose-normalized peak plasma concentration ( Cmax ) and AUC 
    Output:
    
Simvastatin has an extensive first-pass effect in the intestinal wall , whereas atorvastatin has a smaller intestinal first-pass effect .
The interaction with simvastatin seems mainly driven by CYP3A4 inhibition at the intestinal level , whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition .
The interaction of CYP3A4 inhibitor with simvastatin has been more pronounced compared with atorvastatin .
From the current data , atorvastatin seems to be a safer CYP3A4-statin for comedication with DHP-CCB .
There is no convincing evidence that amlodipine is an unusual DHP-CCB , either as a precipitant drug or as an object drug , from the perspective of CYP3A4-mediated drug metabolism .
Amlodipine may have interactions with CYP3A5 in addition to CYP3A4 , which may explain its particular characteristics in comparison with other DHP-CCBs .