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PubMed1996

Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver.

Acyl glucuronides are reactive electrophilic metabolites and in vivo are readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to proteins. The isolated perfused liver preparation, using male Sprague-Dawley rats, was used to examine the hepatic disposition of the fibrate hypolipidemic agent gemfibrozil and its acyl glucuronide metabolite, 1-O-gemfibrozil-beta-D-glucuronide. Using a recirculating design, erythrocyte-free perfusion medium containing 1% (w/v) albumin was delivered to the liver via the portal vein at a flow rate of 30 ml/min, and for each experiment was spiked with either gemfibrozil (N = 4) or 1-O-gemfibrozil-beta-D-glucuronide (N = 4) at initial concentrations of 120 microM and 21 microM, respectively. In the gemfibrozil perfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio of gemfibrozil, and the fraction of eliminated gemfibrozil excreted in bile as the glucuronide conjugate were 2.73 (0.30) ml/min, 76.9 (5.6) min, 0.091 (0.012), and 0.347 (0.154), respectively. In the 1-O-gemfibrozil-beta-D-glucuronide perfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio, and fraction excreted in bile as the glucuronide conjugate were 19.5 (2.1) ml/min, 8.7 (0.9) min, 0.649 (0.068), and 0.534 (0.077), respectively. The higher hepatic extraction ratio for 1-O-gemfibrozil-beta-D-glucuronide could mostly be attributed to its higher unbound fraction in perfusate (0.182), compared with that of the parent drug (0.004), because the conjugate had a lower intrinsic clearance (305 ml/min) compared with the aglycone (751 ml/min). Control perfusions, conducted in the absence of a liver, showed negligible degradation of 1-O-gemfibrozil-beta-D-glucuronide over 90 min. However, in the presence of a liver, approximately 25% of 1-O-gemfibrozil-beta-D-glucuronide added to perfusate was hydrolyzed to gemfibrozil over 90 min. The study demonstrates the importance of the liver in the formation, uptake, hydrolysis, and excretion of 1-O-gemfibrozil-beta-D-glucuronide.

Animals↗
PubMed2003

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide.

AIMS/HYPOTHESIS: Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide. METHODS: In a randomised crossover study, 12 healthy volunteers received twice daily for 3 days either 600 mg gemfibrozil, 100 mg itraconazole (first dose 200 mg), both gemfibrozil and itraconazole, or placebo. On day 3 they ingested a 0.25 mg dose of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 h and serum insulin and C-peptide concentrations for 3 h postdose. RESULTS: Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5- to 15.0-fold; p<0.001) and prolonged its half-life (t(1/2)) from 1.3 to 3.7 h (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1- to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9- to 24.7-fold) and prolonged the t(1/2) of repaglinide to 6.1 h (p<0.001). Plasma repaglinide concentration at 7 h was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<0.001). Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide; i.e., repaglinide became a long-acting and stronger antidiabetic. CONCLUSION/INTERPRETATION: Clinicians should be aware of this previously unrecognised and potentially hazardous interaction between gemfibrozil and repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. If the combination is considered necessary, repaglinide dosage should be greatly reduced and blood glucose concentrations carefully monitored.

Adult↗
PubMed1995

Reactivity of gemfibrozil 1-o-beta-acyl glucuronide. Pharmacokinetics of covalently bound gemfibrozil-protein adducts in rats.

Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and mediate the covalent binding of many acidic drugs to endogenous proteins. Gemfibrozil is extensively metabolized to gemfibrozil acyl glucuronide in humans and rats. The aims of this study were to demonstrate the reactivity of gemfibrozil glucuronide, determine whether gemfibrozil formed covalently bound protein adducts in vivo, describe the pharmacokinetics of adduct formation, and examine the role of gemfibrozil glucuronide in adduct formation. Rats were administered 150 mg/kg gemfibrozil daily for up to 37 days and killed 1, 2, 5, 10, 19, and 37 days after commencement of dosing, and 1, 2, 3, 8, 17, and 30 days after cessation of dosing. Plasma, liver, kidney, and heart were examined for adduct formation. Plasma was quantitatively the most important site for formation of gemfibrozil-protein adducts with mean (SE) steady-state concentrations of 31.40 (2.40) ng/mg protein attained by approximately the 10th day of dosing. Adduct half-life in plasma was 3.1 days, consistent with the elimination half-life of albumin. Mean (SE) kidney, liver, and heart steady-state adduct concentrations were 2.13 (0.11), 0.89 (0.35), and 0.95 (0.07) ng/mg protein, respectively. The rate of gemfibrozil-protein adduct accumulation seemed greatest in liver, but was similar in kidney and plasma, with approximately 2x, 16x, and 30x accumulation, respectively, over the dosing interval. In all tissues, adduct half-lives were significantly greater than those of the noncovalently bound gemfibrozil or gemfibrozil glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group.

OBJECTIVE: To provide a direct comparison of agents that raise plasma levels of high-density lipoprotein cholesterol (HDL-C) to help devise strategies for coronary risk reduction. METHODS: In a multicenter, randomized, double-blind trial, we compared the effects of extended-release niacin (Niaspan), at doses increased sequentially from 1000 to 2000 mg at bedtime, with those of gemfibrozil, 600 mg given twice daily, in raising low levels of HDL-C. Enrollment criteria included an HDL-C level of 1.03 mmol/L or less (< or =40 mg/dL), a low-density lipoprotein cholesterol level of 4.14 mmol/L or less (< or =160 mg/dL) or less than 3.36 mmol/L (<130 mg/dL) with atherosclerotic disease, and a triglyceride level of 4.52 mmol/L or less (< or =400 mg/dL). RESULTS: Among 173 patients, 72 (82%) of the 88 assigned to Niaspan treatment and 68 (80%) of the 85 assigned to gemfibrozil treatment completed the study. Niaspan, at 1500 and 2000 mg, vs gemfibrozil raised the HDL-C level more (21% and 26%, respectively, vs 13%), raised the apolipoprotein A-I level more (9% and 11% vs 4%), reduced the total cholesterol-HDL-C ratio more (-17% and -22% vs -12%), reduced the lipoprotein(a) level (-7% and -20% vs no change), and had no adverse effect on the low-density lipoprotein cholesterol level (2% and 0% change vs a 9% increase). Significance levels for comparisons between medications ranged from P<.001 to P<.02. Gemfibrozil reduced the triglyceride level more than Niaspan (P<.001 to P = .06, -40% for gemfibrozil vs -16% to -29% for Niaspan, 1000 to 2000 mg). Effects on plasma fibrinogen levels were significantly favorable for Niaspan compared with gemfibrozil (P<.02), as gemfibrozil increased the fibrinogen level (from 5% to 9%) and Niaspan tended to decrease the fibrinogen level (from -1% to -6%). CONCLUSIONS: In patients with a low baseline HDL-C level, Niaspan at its higher doses provided up to 2-fold greater HDL-C increases, decreases in lipoprotein(a), improvements in lipoprotein cholesterol ratios, and lower fibrinogen levels compared with gemfibrozil. Gemfibrozil gave a greater triglyceride reduction but also increased the low-density lipoprotein cholesterol level, which did not occur with Niaspan.

Adult↗
PubMed1999

The effect of gemfibrozil on lipid profile and glucose metabolism in hypertriglyceridaemic well-controlled non-insulin-dependent diabetic patients. For the Gemfibrozil Study Group.

We assessed the efficacy of gemfibrozil therapy on lipid profile and glucose metabolism in a large cohort of (type 2) non-insulin-dependent diabetic patients. We enrolled 217 type 2 diabetic patients with plasma triglyceride concentrations equal to or above 2 mmol/l: 110 were randomized to gemfibrozil (600 mg twice daily) and 107 to placebo treatment in a double blind fashion. Each treatment was followed for 20 weeks. To assess postprandial glucose metabolism and insulin secretion, at time 0 and 20 weeks, a standard meal containing 12.5 g of proteins, 40.1 g of carbohydrate, 10 g of lipids was given. No differences in demographic characteristics were observed between patients randomized either to gemfibrozil or to placebo therapy. No differences were observed in total cholesterol and LDL-cholesterol concentration changes between the baseline observations and week 20 of both treatments. At variance, both treatments significantly increased HDL cholesterol. Gemfibrozil treatment significantly decreased plasma triglyceride concentration from 316+/-84 to 214+/-82 mg/dl (P < 0.001), whereas with placebo triglyceride levels increased from 318 + 93 to 380 + 217 mg/dl. No changes were observed in non-esterified fatty acid concentrations or in fasting plasma glucose concentrations, in HbA(1C) values, insulin and C-peptide concentrations. Gemfibrozil treatment: 1) significantly reduces circulating triglyceride concentration; 2) does not significantly affect cholesterol concentration; 3) does not worsen glucose metabolism.

Blood Glucose↗
PubMed1996

[Bioanalysis of gemfibrozil. Comparative human pharmacokinetics of 300 mg of gemfibrozil-containing Innogem and Lopid capsules].

Comparative pharmacokinetic study was performed in 19 healthy male volunteers in a single-dose, randomized, two way cross-over trial on two preparations of gemfibrozil (Innogem and Lopid capsules) each of them containing 300 mg active ingredient. After administration either the test preparation (Innogem, EGIS Pharmaceuticals Ltd.,) or the reference preparation (Lopid, Parke-Davis) in human, the plasma concentration of gemfibrozil was determined by validated HPLC-UV (225 nm) bioanalytical method. After the relatively simple liquid-liquid extraction of the plasma samples the separation was carried out under isocratic condition on Nucleosil 10, C-18 column. On the basis of the validation process the limit of quantitation (LOQ), of the HPLC method was 250 ng/0.5 ml. All the validation parameters fell within the internationally accepted range. The comparison of individual pharmacokinetic parameters (AUC0-16, AUC0-infinity Cmax, tmax) of the two capsule preparations was accomplished by three-way analysis of variance (ANOVA), Wilcoxon's, Westlake's, Schuirmann's and Hauck-Anderson's method as well as by the calculation of confidence intervals on the ratio of test/reference values. The relative bioavailability of Innogem with respect to Lopid 300 mg capsule for AUC0-infinity was 104.06 +/- 21.61%. No statistically significant difference was found in the clinical results and between the pharmacokinetic parameters calculated from plasma concentration-time curves indicating that the two gemfibrozil preparations were bioequivalent after single administration.

Analysis of Variance↗
PubMed2004

Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil.

A serious pharmacokinetic interaction between cerivastatin (CER) and gemfibrozil (GEM) has been reported. In the present study, we examined the inhibitory effects of GEM and its metabolites, M3 and gemfibrozil 1-O-beta-glucuronide (GEM-1-O-glu), on the uptake of CER by human organic anion transporting polypeptide 2 (OATP2)-expressing cells and its metabolism in cytochrome P450 expression systems. Uptake studies showed that GEM and GEM-1-O-glu significantly inhibited the OATP2-mediated uptake of CER with IC(50) values of 72 and 24 microM, respectively. They also inhibited the CYP2C8-mediated metabolism of CER with IC(50) values of 28 and 4 microM, respectively, whereas M3 had no effects. GEM and GEM-1-O-glu minimally inhibited the CYP3A4-mediated metabolism of CER. The IC(50) values of GEM and GEM-1-O-glu for the uptake and the metabolism of CER obtained in the present study were lower than their total, and not unbound, plasma concentrations. However, considering the possibly concentrated high unbound concentrations of GEM-1-O-glu in the liver and its relatively larger plasma unbound fraction compared with GEM itself, the glucuronide inhibition of the CYP2C8-mediated metabolism of CER appears to be the main mechanism for the clinically relevant drug-drug interaction. Previously reported clinical drug interaction studies showing that coadministration of GEM with pravastatin or pitavastatin, both of which are known to be cleared from the plasma by the uptake transporters in the liver, only minimally (less than 2-fold) increased the area under the plasma concentration-time curve of these statins, also supported our present conclusion.

Aryl Hydrocarbon Hydroxylases↗
PubMed1990

Apparent reduced absorption of gemfibrozil when given with colestipol.

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half-life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 +/- 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 +/- 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t-test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 +/- 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 +/- 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half-life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.

Aged↗
PubMed2005

Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions.

Gemfibrozil more potently inhibits CYP2C9 than CYP2C8 in vitro, and yet the opposite inhibitory potency is observed in the clinic. To investigate this apparent paradox, we evaluated both gemfibrozil and its major metabolite, an acyl-glucuronide (gemfibrozil 1-O-beta-glucuronide) as direct-acting and metabolism-dependent inhibitors of the major drug-metabolizing cytochrome P450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) in human liver microsomes. Gemfibrozil most potently inhibited CYP2C9 (IC50 of 30 microM), whereas gemfibrozil glucuronide most potently inhibited CYP2C8 (IC50 of 24 microM). Unexpectedly, gemfibrozil glucuronide, but not gemfibrozil, was found to be a metabolism-dependent inhibitor of CYP2C8 only. The IC50 for inhibition of CYP2C8 by gemfibrozil glucuronide decreased from 24 microM to 1.8 microM after a 30-min incubation with human liver microsomes and NADPH. Inactivation of CYP2C8 by gemfibrozil glucuronide required NADPH, and proceeded with a K(I) (inhibitor concentration that supports half the maximal rate of enzyme inactivation) of 20 to 52 microM and a k(inact) (maximal rate of inactivation) of 0.21 min(-1). Potent inhibition of CYP2C8 was also achieved by first incubating gemfibrozil with alamethicin-activated human liver microsomes and UDP-glucuronic acid (to form gemfibrozil glucuronide), followed by a second incubation with NADPH. Liquid chromatography-tandem mass spectrometry analysis established that human liver microsomes and recombinant CYP2C8 both convert gemfibrozil glucuronide to a hydroxylated metabolite, with oxidative metabolism occurring on the dimethylphenoxy moiety (the group furthest from the glucuronide moiety). The results described have important implications for the mechanism of the clinical interaction reported between gemfibrozil and CYP2C8 substrates such as cerivastatin, repaglinide, rosiglitazone, and pioglitazone.

Alamethicin↗
PubMed2002

Gemfibrozil, a lipid-lowering drug, inhibits the induction of nitric-oxide synthase in human astrocytes.

Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha), we investigated the role of PPAR-alpha in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of DeltahPPAR-alpha, the dominant-negative mutant of human PPAR-alpha. However, DeltahPPAR-alpha was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-alpha. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-gamma (IFN-gamma) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to gamma-activation site (GAS), nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein beta (C/EBPbeta); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1beta and IFN-gamma induced the activation of NF-kappaB, AP-1, C/EBPbeta, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-kappaB, AP-1, and C/EBPbeta but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by inhibiting the activation of NF-kappaB, AP-1, and C/EBPbeta and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in neuroinflammatory diseases.

Astrocytes↗
PubMed2006

The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone.

OBJECTIVE: Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone. METHODS: In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes. RESULTS: The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (C(max)) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethyl-zopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve (AUC(0)-infinity) values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 microM) and itraconazole (8 microM) decreased the elimination rate of zopiclone enantiomers by about 65-95%, while montelukast (16 microM), gemfibrozil (200 microM) and sulfaphenazole (10 microM) had no appreciable effect. CONCLUSIONS: Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded.

Adult↗
PubMed1993

Effect of gemfibrozil on high density lipoprotein subspecies in non-insulin dependent diabetes mellitus. Relations to lipolytic enzymes and to the cholesteryl ester transfer protein activity.

Twenty patients (18 men, 2 women) with non-insulin dependent diabetes mellitus (NIDDM) were randomized to receive either gemfibrozil 1200 mg daily or placebo for 3 months in a double-blind study. The effect of gemfibrozil on plasma HDL subfraction distribution was studied with sequential and density gradient ultracentrifugation and in gradient gel electrophoresis. The concentrations of apo A-I, apo A-II, Lp A-I and Lp A-I:A-II particles were measured. Postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities and plasma cholesteryl ester transfer protein (CETP) activities were also determined. Gemfibrozil increased the concentration of HDL cholesterol (P < 0.01), which was due to the rise of HDL3 cholesterol (+16%), while in the placebo group these values remained unchanged. Gemfibrozil increased the concentrations of apo A-I(+12.6%, NS), apo A-II (+28.2%, P < 0.01) and Lp A-I:A-II particles (+21.6%, P < 0.06) but there were no changes in the placebo group. Neither gemfibrozil nor placebo had any effect on the concentration of Lp A-I particles. As determined by density-gradient ultracentrifugation, gemfibrozil increased the concentration of cholesterol in the most dense HDL fractions (mean density 1.193 g/ml, +22%, P < 0.05 and mean density 1.158 g/ml, +19.3%, P < 0.05). In gradient gel electrophoresis, the gemfibrozil-induced elevations of the cholesterol and protein were most pronounced in the HDL3a (8.8-8.2 nm) region. Gemfibrozil increased LPL and HL activities by 14.7% (P < 0.05) and by 18.8% (P < 0.01), respectively, while in the placebo group LPL and HL activities remained unchanged. Plasma CETP activity was also increased during gemfibrozil treatment while in the placebo group it remained unchanged. We conclude that gemfibrozil causes multiple changes in plasma HDL metabolism. The gemfibrozil-induced elevation of HDL3 and dense HDL subpopulations may reflect the concerted action of LPL, HL and CETP on plasma HDL metabolism.

Apolipoproteins↗
PubMed2004

The effect of gemfibrozil on the pharmacokinetics of rosuvastatin.

BACKGROUND: Coadministration of statins and gemfibrozil is associated with an increased risk for myopathy, which may be due in part to a pharmacokinetic interaction. Therefore the effect of gemfibrozil on rosuvastatin pharmacokinetics was assessed in healthy volunteers. Rosuvastatin has been shown to be a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. The effect of gemfibrozil on rosuvastatin uptake by cells expressing OATP2 was also examined. METHODS: In a randomized, double-blind, 2-period crossover trial, 20 healthy volunteers were given oral doses of gemfibrozil, 600 mg, or placebo twice daily for 7 days. On the fourth morning of each dosing period, a single oral dose of rosuvastatin, 80 mg, was coadministered. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin-lactone were measured. In addition, the effect of gemfibrozil on the uptake of radiolabeled rosuvastatin by OATP2-transfected Xenopus oocytes was studied. RESULTS: Gemfibrozil increased the rosuvastatin area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration [AUC(0-t)] 1.88-fold (90% confidence interval, 1.60-2.21) and the maximum observed rosuvastatin plasma concentration (C(max)) 2.21-fold (90% confidence interval, 1.81-2.69) compared with placebo. N-desmethyl rosuvastatin AUC(0-t) and C(max) decreased by 48% and 39%, respectively. Pharmacokinetics of rosuvastatin-lactone was unchanged. The in vitro results indicate that the maximum gemfibrozil inhibition of rosuvastatin OATP2-mediated uptake was 50%; the inhibition constant for the inhibitory process was 4.0 +/- 1.3 micromol/L. CONCLUSIONS: Gemfibrozil increased rosuvastatin plasma concentrations approximately 2-fold, which is similar to the effect of gemfibrozil on pravastatin, simvastatin acid, and lovastatin acid plasma concentrations and substantially less than the effect observed for cerivastatin. Gemfibrozil inhibition of OATP2-mediated rosuvastatin hepatic uptake may contribute to the mechanism of the drug-drug interaction. Care is warranted when gemfibrozil is coadministered with rosuvastatin and other statins.

Administration, Oral↗
PubMed2005

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.

BACKGROUND AND OBJECTIVE: The thiazolidinedione antidiabetic drug pioglitazone is metabolized mainly by cytochrome P450 (CYP) 2C8 and CYP3A4 in vitro. Our objective was to study the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone to determine the role of these enzymes in the fate of pioglitazone in humans. METHODS: In a randomized, double-blind, 4-phase crossover study, 12 healthy volunteers took either 600 mg gemfibrozil or 100 mg itraconazole (first dose, 200 mg), both gemfibrozil and itraconazole, or placebo twice daily for 4 days. On day 3, they received a single dose of 15 mg pioglitazone. Plasma drug concentrations and the cumulative excretion of pioglitazone and its metabolites into urine were measured for up to 48 hours. RESULTS: Gemfibrozil alone raised the mean total area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of pioglitazone 3.2-fold (range, 2.3-fold to 6.5-fold; P < .001) and prolonged its elimination half-life (t (1/2) ) from 8.3 to 22.7 hours ( P < .001) but had no significant effect on its peak concentration (C max ) compared with placebo (control). Gemfibrozil increased the 48-hour excretion of pioglitazone into urine by 2.5-fold ( P < .001) and reduced the ratios of the active metabolites M-III and M-IV to pioglitazone in plasma and urine. Gemfibrozil decreased the area under the plasma concentration-time curve from time 0 to 48 hours [AUC(0-48)] of the metabolites M-III and M-IV by 42% ( P < .05) and 45% ( P < .001), respectively, but their total AUC(0-infinity) values were reduced by less or not at all. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. The mean area under the concentration versus time curve to 49 hours [AUC(0-49)] of itraconazole was 46% lower ( P < .001) during the gemfibrozil-itraconazole phase than during the itraconazole phase. CONCLUSIONS: Gemfibrozil elevates the plasma concentrations of pioglitazone, probably by inhibition of its CYP2C8-mediated metabolism. CYP2C8 appears to be of major importance and CYP3A4 of minor importance in pioglitazone metabolism in vivo in humans. Concomitant use of gemfibrozil with pioglitazone may increase the effects and risk of dose-related adverse effects of pioglitazone. However, studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction.

Administration, Oral↗
PubMed2004

Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil.

OBJECTIVE: Ezetimibe is a novel lipid-lowering drug that prevents intestinal absorption of dietary and biliary cholesterol leading to significant reduction in total-C, LDL-C, Apo B, and TG and increases in HDL-C in patients with hypercholesterolemia. Gemfibrozil, a fibric acid derivative, is an effective lipid-modulating agent that increases serum high-density lipoprotein cholesterol and decreases serum TG. The objective of this study was to evaluate the potential for a pharmacokinetic (PK) interaction between ezetimibe and gemfibrozil. METHODS: This was a randomized, open-label, 3-way crossover, multiple-dose study in 12 healthy adult male volunteers. All subjects received the following 3 treatments orally for 7 days: ezetimibe 10 mg once daily, gemfibrozil 600 mg every 12 hours, and ezetimibe 10 mg once daily plus gemfibrozil 600 mg every 12 hours. A washout period of > or = 7 days separated the 3 treatments. In each treatment, blood samples were collected on day 7 to assess the steady-state PK of ezetimibe and gemfibrozil. The oral bioavailability of ezetimibe coadministered with gemfibrozil relative to each drug administered alone was evaluated with an analysis-of-variance model. RESULTS: Ezetimibe was rapidly absorbed and extensively conjugated to its glucuronide metabolite. Ezetimibe did not alter the bioavailability (based on AUC) of gemfibrozil. The mean AUC0-12 of gemfibrozil was 74.7 and 74.1 microg h/ml with and without ezetimibe coadministration, respectively (log-transformed geometric mean ratio (GMR) = 99.2; 90% confidence interval (CI) = 92 - 107%). Conversely, gemfibrozil significantly (p < 0.05) increased the plasma concentrations of ezetimibe and total ezetimibe (i.e. ezetimibe plus ezetimibe-glucuronide). Exposure to ezetimibe and total ezetimibe was increased approximately 1.4-fold and 1.7-fold, respectively (CI = 109 - 173% for ezetimibe and 142 - 190% for total ezetimibe), however, this increase was not considered to be clinically relevant. Ezetimibe and gemfibrozil administered alone or concomitantly for 7 days was well tolerated. CONCLUSIONS: The coadministration of ezetimibe and gemfibrozil in patients is unlikely to cause a clinically significant drug interaction. The coadministration of these agents is a promising approach for patients with mixed dyslipidemia. Additional clinical studies are warranted.

Administration, Oral↗
PubMed2005

Interconversion pharmacokinetics of simvastatin and its hydroxy acid in dogs: effects of gemfibrozil.

PURPOSE: To characterize the pharmacokinetics of simvastatin (SV) and simvastatin acid (SVA), a lactone-acid pair known to undergo reversible metabolism, and to better understand mechanisms underlying pharmacokinetic interactions observed between SV and gemfibrozil. METHODS: Pharmacokinetic studies were conducted after intravenous administration of SV and SVA to dogs pretreated with a vehicle or gemfibrozil. In vitro metabolism of SVA in dog hepatocytes as well as in vitro hepatic and plasma conversion of SV/SVA were investigated in the absence and presence of gemfibrozil. RESULTS: In control animals, the irreversible elimination clearances of SV (CL10) and SVA (CL20) were 10.5 and 18.6 ml min(-1) kg(-1), respectively. The formation clearance of SVA from SV (CL12 = 4.8 ml min(-1) kg(-1)) was 8-fold greater than that of SV from SVA (CL21 = 0.6 ml min(-1) kg(-1)), and the recycled fraction was relatively minor (0.009). In gemfibrozil-treated animals, CL10 was essentially unchanged, whereas CL12, CL20, CL21, and recycled fraction were significantly decreased to 2.9, 9, 0.14 ml min(-1) kg(-1), and 0.003, respectively. In control dogs, values for real volume of distribution at steady state (Vss,real) of SV (2.3 L kg(-1)) were much larger than the corresponding values of SVA (0.3 L kg(-1)). Gemfibrozil treatment did not affect Vss,real of either SV or SVA. In dog hepatocytes, gemfibrozil modestly affected the formation of CYP3A-mediated oxidative metabolites (IC50 > 200 microM) and beta-oxidative products (IC5) approximately 100 microM), but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of an SVA beta-oxidation product (IC50 = 18 microM). In in vitro dog and human liver S9 and plasma, hydrolysis of SV to SVA was much faster than that of SVA to SV. Gemfibrozil (250 microM) had a minimal inhibitory effect on the hydrolysis of either SV to SVA or SVA to SV in dog and human liver S9, but had a significant ( approximately 60%) inhibitory effect on the SV to SVA hydrolysis in both dog and human plasma. CONCLUSIONS: In dogs, the interconversion process favored the formation of SVA and was less efficient than the irreversible elimination processes of SV and SVA. Treatment with gemfibrozil did not affect the distribution of SV/SVA, but rather affected the elimination of SVA and the SV/SVA interconversion processes. Gemfibrozil decreased CL20 and CL21 likely via its inhibitory effect on the glucuronidation of SVA, and not on the CYP3A-mediated oxidative metabolism of SV or SVA, the beta-oxidation of SVA, nor the SVA to SV hydrolysis. The decrease in CL12 might be due in part to the inhibitory effect of gemfibrozil on SV to SVA hydrolysis in plasma. Similar rationales may also be applicable to studies in humans and/or other statin lactone-acid pairs.

Animals↗
PubMed2000

Plasma concentrations of active simvastatin acid are increased by gemfibrozil.

BACKGROUND: Concomitant treatment with simvastatin and gemfibrozil, two lipid-lowering drugs, has been associated with occurrence of myopathy in case reports. The aim of this study was to determine whether gemfibrozil affects the pharmacokinetics of simvastatin and whether it affects CYP3A4 activity in vitro. METHODS: A double-blind, randomized crossover study with two phases (placebo and gemfibrozil) was carried out. Ten healthy volunteers were given gemfibrozil (600 mg twice daily) or placebo orally for 3 days. On day 3 they ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin and simvastatin acid were measured up to 12 hours. In addition, the effect of gemfibrozil (0 to 1,200 micromol/L) on midazolam 1'-hydroxylation, a CYP3A4 model reaction, was investigated in human liver microsomes in vitro. RESULTS: Gemfibrozil increased the mean total area under the plasma concentration-time curve of simvastatin [AUC(0-infinity)] by 35% (P < .01) and the AUC(0-infinity) of simvastatin acid by 185% (P < .001). The elimination half-life of simvastatin was increased by 74% (P < .05), and that of simvastatin acid was increased by 51% (P < .01) by gemfibrozil. The peak concentration of simvastatin acid was increased by 112%, from 3.20 +/- 2.73 ng/mL to 6.78 +/- 4.67 ng/mL (mean +/- SD; P < .01). In vitro, gemfibrozil showed no inhibition of midazolam 1'-hydroxylation. CONCLUSIONS: Gemfibrozil increases plasma concentrations of simvastatin and, in particular, its active form, simvastatin acid, suggesting that the increased risk of myopathy in combination treatment is, at least partially, of a pharmacokinetic origin. Because gemfibrozil does not inhibit CYP3A4 in vitro, the mechanism of the pharmacokinetic interaction is probably inhibition of non-CYP3A4-mediated metabolism of simvastatin acid.

Adult↗
PubMed2002

Gemfibrozil greatly increases plasma concentrations of cerivastatin.

BACKGROUND: Concomitant use of gemfibrozil with statins, particularly with cerivastatin, increases the risk of rhabdomyolysis, but the mechanism of this potentially fatal drug interaction remains unclear. Our aim was to study the effect of gemfibrozil on cerivastatin pharmacokinetics. METHODS: In a randomized, double-blind crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 3 days. On day 3, each subject ingested a single 0.3-mg dose of cerivastatin. Plasma concentrations of cerivastatin, its metabolites, and gemfibrozil were measured up to 24 hours. RESULTS: During gemfibrozil treatment, the area under the plasma concentration-time curve [AUC(0-infinity)] of parent cerivastatin was on average 559% (range, 138% to 995%; P =.0002) and the peak concentration in plasma was 307% (138% to 809%; P =.0019) of the corresponding values in the placebo phase. Gemfibrozil increased the AUC(0-infinity) of cerivastatin lactone, on average, to 440% (94% to 594%; P =.0024) and that of metabolite M-1 to 435% (216% to 802%; P =.0002) of the control (placebo) values, whereas the AUC(0-24) of metabolite M-23 was decreased to 22% (11% to 74%; P =.0017). CONCLUSIONS: Gemfibrozil greatly increases plasma concentrations of cerivastatin, cerivastatin lactone, and metabolite M-1, whereas the level of metabolite M-23 is markedly reduced by gemfibrozil. Gemfibrozil therefore inhibits the formation of M-23, which is thought to be dependent on CYP2C8. The increased exposure to cerivastatin in the presence of gemfibrozil may explain the high incidence of myopathy observed with this combination, although the role of pharmacodynamic interactions between these 2 agents cannot be excluded.

Administration, Oral↗