Biomedical subjects

P J Neuvonen

Publications and source records attributed to P J Neuvonen.

At least 91 records · Page 5Linked to original sources

PubMed1999

Lack of effect of terfenadine on the pharmacokinetics of the CYP3A4 substrate buspirone.

The effects of terfenadine, a non-sedating antihistamine on the pharmacokinetics and pharmacodynamics of buspirone, a CYP3A4 substrate, were investigated in a randomised, placebo-controlled, two-phase cross-over study. Ten healthy volunteers took either 120 mg terfenadine or matched placebo orally once daily for 3 days. On day 3, 10 mg buspirone was taken orally. Plasma concentrations of buspirone were measured up to 18 hr and its pharmacodynamic effects up to 8 hr. Terfenadine slightly but not significantly increased plasma concentrations of buspirone. No psychomotor deterioration was observed during the terfenadine phase. In conclusion, terfenadine did not significantly affect the pharmacokinetics of buspirone, a CYP3A4 substrate shown to be very susceptible to interactions with CYP3A4 inhibitors. Thus, terfenadine is expected to have little effect on the pharmacokinetics of CYP3A4 substrates in general.

Adult↗

PubMed1999

Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers.

A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double-blind, randomized, two-phase cross-over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. Itraconazole increased the total area under the plasma methylprednisolone concentration-time curve (AUC(0-infinity) 2.6-fold) (P<0.001), while the AUC (12-24) of methylprednisolone was increased 12.2-fold (P<0.001). The systemic clearance of methylprednisolone during the itraconazole phase was 40% of that during the placebo phase (P<0.01). The volume of distribution of methylprednisolone was not affected by itraconazole. The mean elimination half-life of methylprednisolone was increased from 2.1+/-0.3 hr to 4.8+/-0.8 hr (P<0.001) by itraconazole. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hr after the administration of methylprednisolone, was only about 9% of that during the placebo phase (11.0+/-9.0 ng/ml versus 117+/-49.2 ng/ml; P<0.001). In conclusion, itraconazole decreases the clearance and increases the elimination half-life of intravenously administered methylprednisolone, resulting in greatly increased exposure to methylprednisolone during the night time and in enhanced adrenal suppression. Care should be taken when itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with methylprednisolone.

Administration, Oral↗

PubMed1999

Fluvoxamine is a more potent inhibitor of lidocaine metabolism than ketoconazole and erythromycin in vitro.

CYP3A4 is generally believed to be the major CYP enzyme involved in the biotransformation of lidocaine in man; however, recent in vivo studies suggest that this may not be the case. We have examined the effects of the CYP3A4 inhibitors erythromycin and ketoconazole and the CYP1A2 inhibitor fluvoxamine on the N-deethylation, i.e. formation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocaine by human liver microsomes. The experiments were carried out at lidocaine concentrations of 5 microM (clinically relevant concentration) and 800 microM. The formation of both MEGX and 3-hydroxylidocaine was best described by a two-enzyme model. At 5 microM of lidocaine, fluvoxamine was a potent inhibitor of the formation of MEGX (IC50 1.2 microM). Ketoconazole and erythromycin also showed an inhibitory effect on MEGX formation, but ketoconazole (IC50 8.5 microM) was a much more potent inhibitor than erythromycin (IC50 200 microM). At 800 microM of lidocaine, fluvoxamine (IC50 20.7 microM) and ketoconazole (IC50 20.4 microM) displayed a modest inhibitory effect on MEGX formation, whereas erythromycin was a weak inhibitor (IC50 >250 microM). The 3-hydroxylation of lidocaine was potently inhibited by fluvoxamine at both lidocaine concentrations (IC50 0.16 microM at 5 microM and 1.8 microM at 800 microM). Erythromycin and ketoconazole showed a clear inhibitory effect on the 3-hydroxylation of lidocaine at 5 microM of lidocaine (IC50 9.9 microM and 13.9 microM, respectively), but did not show a consistent effect at 800 microM of lidocaine (IC50 >250 microM and 75.0 microM, respectively). Although further studies are needed to elucidate the role of distinct CYP enzymes in the biotransformation of lidocaine in humans, the findings of this study suggest that while both CYP1A2 and CYP3A4 are involved in the metabolism of lidocaine by human liver microsomes, CYP1A2 is the more important isoform at clinically relevant lidocaine concentrations.

Anesthetics, Local↗

PubMed1998

The pharmacokinetics of oxybutynin is unaffected by gender and contraceptive steroids.

OBJECTIVE AND METHODS: The effect of gender and concomitant use of contraceptive steroids on the absorption and metabolism of oxybutynin was investigated in 49 healthy volunteers, 24 females and 25 males. Serum concentrations of oxybutynin and its active metabolite, N-desethyloxybutynin, were measured for up to 48 h after ingestion of a single dose of 10 mg oxybutynin. RESULTS: Intake of oral contraceptive steroids had no significant effect on the pharmacokinetic parameters of oxybutynin or its metabolite. Both in males and females, the mean area under the curve (AUC0-t) of N-desethyloxybutynin was about 13 times higher and the peak concentration (Cmax) 15 to 19 times higher than the AUC0-t and Cmax of the parent oxybutynin, with no significant differences between males and females. CONCLUSIONS: The pharmacokinetics of orally administered oxybutynin shows a considerable interindividual variability, but is unaffected by gender and use of contraceptive steroids.

Administration, Oral↗

PubMed1998

Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174.

OBJECTIVE: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. METHODS: A randomised, double-blind, three-phase crossover study design was used. Eleven healthy volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg, fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo (control). On day 4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. RESULTS: The mean peak plasma concentration (Cmax) and area under the curve [AUC(0-infinity)] of E-3174 were significantly decreased by fluconazole to 30% and to 47% of their control values, respectively, and the t1/2 was increased to 167%. Fluconazole caused only a nonsignificant increase (23-41%) in the AUC and t1/2 of the unchanged losartan. Itraconazole had no significant effect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC(0-infinity)(E-3174)/AUC(0-infinity)losartan was 60% smaller during the fluconazole than during the placebo and itraconazole phases. No clinically significant changes in the effects of losartan on blood pressure and heart rate were observed between fluconazole, itraconazole and placebo phases. CONCLUSION: Fluconazole but not itraconazole interacts with losartan by inhibiting its metabolism to the active metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical significance of the fluconazole losartan interaction is unclear, but the possibility of a decreased therapeutic effect of losartan should be kept in mind.

Adult↗

PubMed1998

The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin.

OBJECTIVE: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. METHODS: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on the last day of itraconazole administration, and 4 days later, and 15 mg 1 day and 4 days after the last dose of rifampicin. The disposition of midazolam and its alpha-hydroxy metabolite was determined and its pharmacodynamic effects were measured. RESULTS: During itraconazole treatment, or 4 days after, alpha-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration time curve (AUC0-infinity) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng x h x ml(-1)), respectively. One day after rifampicin treatment, the AUC0-infinity of midazolam was 2.3% (i.e. 4.4 ng x h x ml(-1)) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0-infinity was still only 13% (i.e. 27.1 ng x h x ml(-1)) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma alpha-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. CONCLUSION: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.

Administration, Oral↗

PubMed1998

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem.

OBJECTIVE: Zolpidem is a short-acting imidazopyridine hypnotic which is biotransformed in humans mainly by CYP3A4. Itraconazole strongly interacts with many substrates of CYP3A4 such as midazolam and triazolam. In this study, the effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem was investigated to uncover a possible clinically significant interaction. METHODS: In a randomized cross-over study with two phases, ten healthy volunteers took either 200 mg itraconazole or placebo once daily for 4 days. A single oral dose of 10 mg zolpidem was given on day 4. Plasma drug concentrations were measured up to 17 h and effects of zolpidem up to 9 h after the ingestion of zolpidem. RESULTS: Itraconazole had no marked effects on the pharmacokinetics of zolpidem; the total area under the plasma zolpidem concentration-time curve (AUC0-infinity) was 34% larger during the itraconazole phase (759 ng x h x ml(-1)) than during the placebo phase (567 ng x h x ml(-1)). Exophoria of the eyes by the Maddox wing test was significantly increased by itraconazole, but the results of the digit symbol substitution test, critical flicker fusion test, postural sway tests and the visual analogue scale tests for subjective drowsiness and overall drug effect did not differ between the phases. CONCLUSION: The pharmacokinetics and pharmacodynamics of zolpidem were not remarkably affected by itraconazole in healthy volunteers. Therefore, unlike triazolam, for example, zolpidem can be used in normal or nearly normal doses together with itraconazole and probably also with other CYP3A4 inhibitors.

Adult↗

PubMed1998

Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole.

OBJECTIVE: We studied a possible pharmacokinetic interaction between clozapine and itraconazole, a potent CYP3A4 inhibitor. METHODS: A double-blind randomized study design was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 200 mg itraconazole or placebo for 7 days. For the next 7 days, itraconazole was changed to placebo and vice versa. Serum concentrations of clozapine and its main metabolite desmethylclozapine were measured on days 0, 3, 7, 10 and 14. RESULTS: Concomitant administration of itraconazole had no significant effect on serum concentrations of clozapine or desmethylclozapine. CONCLUSION: CYP3A4 seems to be of minor importance in clozapine metabolism in humans. Itraconazole, and probably also other inhibitors of CYP3A4, can be used concomitantly with clozapine.

Adult↗

PubMed1998

Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine.

OBJECTIVE: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design. METHODS: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg x kg(-1) was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography. RESULTS: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC(0-11 h) by 45-60%. CONCLUSION: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine.

Adult↗

PubMed1998

Effect of itraconazole on the pharmacokinetics of atorvastatin.

BACKGROUND: Itraconazole, a potent inhibitor of CYP3A4, increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by increasing their serum concentrations. The aim of this study was to characterize the effect of itraconazole on the pharmacokinetics of atorvastatin, a new HMG-CoA reductase inhibitor that is metabolized at least in part by CYP3A4. METHODS: In a randomized, double-blind, two-phase crossover study, 10 healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg atorvastatin was administered orally, and a further dose of 200 mg itraconazole or placebo was taken 24 hours after atorvastatin intake. Serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid and lactone, 4-hydroxyatorvastatin acid and lactone, active and total HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were measured up to 72 hours. RESULTS: Itraconazole increased the area under the concentration--time curve from time zero to 72 hours [AUC(0-72)] and the elimination half-life of atorvastatin acid about threefold (p < 0.001), whereas the peak serum concentration was not significantly changed. The AUC(0-72) of atorvastatin lactone was increased about fourfold (p < 0.001), and the peak serum concentration and half-life were increased more than twofold (p < 0.01). Itraconazole decreased the peak serum concentration and AUC(0-72) of 2-hydroxyatorvastatin acid (p < 0.01) and 2-hydroxyatorvastatin lactone (p < 0.01). Itraconazole significantly (p < 0.01) increased the half-life of 2 hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.6-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively. CONCLUSIONS: Itraconazole has a significant interaction with atorvastatin. The mechanism of increased serum concentrations of atorvastatin and HMG-CoA reductase inhibitors is inhibition of CYP3A4-mediated metabolism of atorvastatin and its metabolites by itraconazole. Concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should be avoided or the dose of atorvastatin should be reduced accordingly.

Adult↗

PubMed1998

Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid.

BACKGROUND: Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A4. We wanted to investigate a possible interaction of grapefruit juice with lovastatin, a cholesterol-lowering agent that is partially metabolized by CY P3A4. METHODS: An open, randomized, two-phase crossover study with an interval of 2 weeks between the phases was carried out. Ten healthy volunteers took either 200 ml double-strength grapefruit juice or water orally three times a day for 2 days. On day 3, each subject ingested 80 mg lovastatin with either 200 ml grapefruit juice or water, and an additional dose of 200 ml was ingested 1/2 and 1 1/2 hours after lovastatin intake. Serum concentrations of lovastatin and lovastatin acid were measured up to 12 hours. RESULTS: Grapefruit juice greatly increased the serum concentrations of both lovastatin and lovastatin acid. The mean peak serum concentration (Cmax) of lovastatin was increased about 12-fold (range, 5.2-fold to 19.7-fold; p < 0.001) and the area under the concentration-time curve [AUC(0-12)] was increased 15-fold (range, 5.7-fold to 26.3-fold; p < 0.001) by grapefruit juice. The mean Cmax and AUC(0-12) of lovastatin acid were increased about fourfold (range, 1.8-fold to 11.5-fold; p < 0.001) and fivefold (range, 2.4-fold to 23.3-fold; p < 0.001) by grapefruit juice, respectively. The half-lives of lovastatin and lovastatin acid remained unchanged. CONCLUSIONS: Grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine. The concomitant use of grapefruit juice with lovastatin and simvastatin should be avoided, or the dose of these 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Acids↗

PubMed1998

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin.

BACKGROUND: Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions. METHODS: The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration. RESULTS: Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase. CONCLUSIONS: Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.

Administration, Oral↗

PubMed1998

Grapefruit juice substantially increases plasma concentrations of buspirone.

BACKGROUND: Buspirone has a low oral bioavailability because of extensive first-pass metabolism. The effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of orally administered buspirone is not known. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 10 mg buspirone with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours after buspirone administration. Timed blood samples were collected up to 12 hours after ingestion, and the effects of buspirone were measured with 6 psychomotor tests up to 8 hours after ingestion. RESULTS: Grapefruit juice increased the mean peak plasma concentration of buspirone 4.3-fold (range, 2-fold to 15.6-fold; P < .01) and the mean area under the plasma buspirone concentration-time curve 9.2-fold (range, 3-fold to 20.4-fold; P < .01). The time of the peak concentration (tmax) of buspirone increased from 0.75 to 3 hours (P < .01), and the elimination half-life (t1/2) was slightly increased (P < .01) by grapefruit juice. A significant increase in the pharmacodynamic effects of buspirone by grapefruit juice was seen only in subjective overall drug effect (P < .01). CONCLUSIONS: Grapefruit juice considerably increased plasma buspirone concentrations. The probable mechanism of this interaction is delayed gastric emptying and inhibition of the cytochrome P450 3A4-mediated first-pass metabolism of buspirone caused by grapefruit juice. Concomitant use of buspirone and at least large amounts of grapefruit juice should be avoided.

Adult↗

PubMed1998

Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole.

BACKGROUND: Methylprednisolone is a widely used glucocorticoid. In this study, a possible interaction of itraconazole, a potent inhibitor of CYP3A4, with orally administered methylprednisolone was examined. METHODS: In this double-blind, randomized, 2-phase crossover study, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a dose of 16 mg methylprednisolone. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined by HPLC up to 24 hours. RESULTS: Itraconazole increased the total area under the plasma methylprednisolone concentration-time curve 3.9-fold compared with placebo (1968 +/- 470 ng.hr/mL versus 520 +/- 125 ng.hr/mL [mean +/- SD]; P < .001). The peak plasma concentration of methylprednisolone was increased 1.9-fold (221 +/- 49 ng/mL versus 118 +/- 25 ng/mL; P < .001), and its elimination half-life was increased 2.4-fold (4.4 +/- 0.7 hours versus 1.9 +/- 0.3 hours; P < .001) by itraconazole. The mean plasma cortisol concentration during the itraconazole phase, measured 24 hours after ingestion of methylprednisolone, was only about 13% of that during the placebo phase (18 +/- 23 ng/mL versus 139 +/- 60 ng/mL; P < .001). CONCLUSIONS: Itraconazole considerably increases plasma concentrations and effects of oral methylprednisolone, probably by inhibiting its CYP3A4-mediated metabolism. Care should be taken if itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with oral methylprednisolone, particularly during long-term use.

Administration, Oral↗

PubMed1998

Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone.

BACKGROUND: Buspirone has an extensive first-pass metabolism, which makes it potentially susceptible to drug interactions. The aim of this study was to investigate possible interactions of buspirone with verapamil and diltiazem. METHODS: In a randomized, placebo-controlled, three-phase crossover study, nine healthy volunteers received either 80 mg verapamil, 60 mg diltiazem, or placebo orally three times a day. On day 2, after the fifth dose, 10 mg buspirone was given orally. Plasma concentrations of buspirone, verapamil, and diltiazem were determined up to 18 hours, and the effects of buspirone were measured up to 8 hours. RESULTS: Verapamil and diltiazem increased the area under the buspirone plasma concentration-time curve [AUC (0-infinity)] 3.4-fold (p < 0.001) and 5.5-fold (p < 0.001), respectively. The peak plasma concentration of buspirone was increased 3.4-fold (p < 0.001) and 4.1-fold (p < 0.001) by verapamil and diltiazem, respectively. The effect of diltiazem on the AUC(0-infinity) of buspirone was significantly (p < 0.05) greater than that of verapamil. The elimination half-life of buspirone was not changed by verapamil and diltiazem. Of the six pharmacodynamic variables, only the subjective overall drug effect of buspirone was significantly increased with verapamil (p < 0.05) and diltiazem (p < 0.05). Side effects of buspirone occurred more often (p < 0.05) with diltiazem than with placebo. CONCLUSIONS: Both verapamil and diltiazem considerably increase plasma buspirone concentrations, probably by inhibiting its CYP3A4-mediated first-pass metabolism. Thus enhanced effects and side effects of buspirone are possible when it is used with verapamil, diltiazem, or other inhibitors of CYP3A4.

Adult↗

PubMed1998

Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors.

BACKGROUND: Simvastatin is a cholesterol-lowering agent that is metabolized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered simvastatin. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 60 mg simvastatin with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 and 1 1/2 hours after simvastatin administration. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and those of active (naive) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. RESULTS: Grapefruit juice increased the mean peak serum concentration (Cmax) of unchanged simvastatin about 9-fold (range, 5.1-fold to 31.4-fold; P < .01) and the mean area under the serum simvastatin concentration-time curve [AUC(0-infinity)] 16-fold (range, 9.0-fold to 37.7-fold; P < .05). The mean Cmax and AUC(0-infinity) of simvastatin acid were both increased about 7-fold (P < .01). Grapefruit juice increased the mean AUC(0-infinity) of active and total HMG-CoA reductase inhibitors 2.4-fold (P < .01) and 3.6-fold (P < .01), respectively. The time of the peak concentration of active and total HMG-CoA reductase inhibitors was increased by grapefruit juice (P < .05). CONCLUSION: Grapefruit juice greatly increased serum concentrations of simvastatin and simvastatin acid and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors. The probable mechanism of this interaction was inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in the small intestine. Concomitant use of grapefruit juice and simvastatin, at least in large amounts, should be avoided, or the dose of simvastatin should be greatly reduced.

Adult↗

PubMed1998

Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.

OBJECTIVE: To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. METHODS: A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. RESULTS: Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours [AUC(0-24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil. CONCLUSIONS: Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used.

Adult↗

PubMed1998

Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole.

BACKGROUND: Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin. METHODS: Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined. RESULTS: In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2 were increased threefold (p < 0.001). In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by itraconazole. There were no differences in the serum concentrations of itraconazole and hydroxyitraconazole between studies I and II. CONCLUSIONS: Itraconazole greatly increased serum concentrations of simvastatin, simvastatin acid, and HMG CoA reductase inhibitors, probably by inhibiting CYP3A-mediated metabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided or its dosage should be greatly reduced.

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