Biomedical subjects

P J Neuvonen

Publications and source records attributed to P J Neuvonen.

At least 73 records · Page 4Linked to original sources

PubMed2000

Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants.

OBJECTIVE: To provide a rational basis for the dosage of fentanyl in newborn infants by determining clearance in the first days of life. STUDY DESIGN: A continuous infusion of fentanyl for 2 to 3 days (10. 5 microg/kg over a 1-hour period followed by 1.5 microg/kg/h) was administered to 38 newborn infants who had undergone ventilation (gestational ages 26 to 42 weeks and birth weights 835 to 3550 g). Fentanyl concentrations were measured in arterial blood samples collected at 2, 12, 24, 48, and 60 hours after the start of fentanyl infusion. Fentanyl levels were correlated with a pain score. RESULTS: The mean (+/-SD) steady-state fentanyl concentration of 2.5 (+/-1) ng/mL achieved between 24 and 48 hours of infusion correlated significantly with the concomitant pain score (r = -0.57, P <.01). The clearance, 11.5 (+/-4.0) mL/min/kg, correlated significantly with the gestational age (r = 0.46, P <.01) and birth weight (r = 0. 48, P <.01). CONCLUSIONS: Because plasma fentanyl clearance increases with maturity, gestational age should be taken into account when fentanyl is administered to newborn infants.

Analgesics, Opioid↗

PubMed2000

Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans.

The roles of cytochrome P-450 (CYP) enzymes in the N-deethylation, i.e., formation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocaine were studied with human liver microsomes and recombinant human CYP isoforms. Both CYP1A2 and CYP3A4 were found to be capable of catalyzing the formation of MEGX and 3-OH-lidocaine. Lidocaine N-deethylation by liver microsomes was strongly inhibited by furafylline (by about 60%) and anti-CYP1A1/2 antibodies (>75%) at 5 microM lidocaine, suggesting that CYP1A2 was the major isoform catalyzing lidocaine N-deethylation at low (therapeutically relevant) lidocaine concentrations. Troleandomycin inhibited the N-deethylation of lidocaine by about 50% at 800 microM lidocaine, suggesting that the role of CYP3A4 may be more important than that of CYP1A2 at high lidocaine concentrations. Chemical inhibition and immunoinhibition studies also indicated that 3-OH-lidocaine formation was catalyzed almost exclusively by CYP1A2, CYP3A4 playing only a minor role. Although the CYP2C9 inhibitor sulfaphenazole (100 microM) inhibited MEGX formation by about 30%, recombinant human CYP2C9 showed very low catalytic activity, suggesting a negligible role for this enzyme in lidocaine N-deethylation. Chemical inhibition studies indicated that CYP2C19, CYP2D6, and CYP2E1 did not play significant roles in the metabolism of lidocaine in vitro. Taken together, these results demonstrate that CYP1A2 and CYP3A4 enzymes are the major CYP isoforms involved in lidocaine N-deethylation. Therefore, the MEGX test (formation of MEGX from lidocaine) is not a suitable marker of hepatic CYP3A4 activity in vivo.

Anti-Arrhythmia Agents↗

PubMed1999

Effect of itraconazole on cerivastatin pharmacokinetics.

OBJECTIVE: To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: A randomized, double-blind, cross-over study design with two phases, which were separated by a washout period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h. RESULTS: Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (Cmax) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC(0-24h) 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC(0-24h) of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC(0- 24h) of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC(0-24h) and t1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole. CONCLUSIONS: Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors.

Adolescent↗

PubMed1999

Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants.

BACKGROUND: Reactive oxygen species have been considered to play a role in several clinical complications in pre-term infants. The aim of this study was to determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term neonates. This information is needed to evaluate the use of N-acetylcysteine as an antioxidant in this patient group. METHODS: N-acetylcysteine was infused intravenously in ten patients (gestational age 24.9-31.0 weeks, weight 500-1384 g) for 24 h (3.4-4.6 mg/kg/h), starting 2.0-11.2 h from birth (study I) and in six patients (gestational age 25.9-29.7 weeks, weight 520-1335 g) for 6 days (0.3-1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N-acetylcysteine and cyst(e)ine concentrations were determined from timed samples taken during (study I and II) and after (study I) the N-acetylcysteine infusion. RESULTS: In study I, the mean elimination half-life of N-acetylcysteine was 11 h (range 7.8-15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h (range 13-62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range 167-1010 ml/kg). The plasma clearance and volume of distribution correlated with weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In study II, the steady-state concentration of N-acetylcysteine was reached in 2-3 days in five of six patients during a constant infusion. CONCLUSIONS: The pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on weight and gestational age. The elimination of N-acetylcysteine is much slower in pre-term new-borns than in adults.

Acetylcysteine↗

PubMed1999

Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride.

BACKGROUND: Grapefruit juice increases the bioavailability of several drugs that are metabolized during first pass by CYP3A4. In this study, the effect of grapefruit juice on the pharmacokinetics of orally administered cisapride was investigated. METHODS: In a randomized, two-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water three times a day for 2 days. On day 3, each subject ingested 10 mg cisapride with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours after cisapride administration. Timed blood samples were collected for 32 hours after cisapride intake, and a standard 12-lead ECG was recorded before the administration of cisapride and 2, 5, 8, and 12 hours later. RESULTS: The mean peak plasma concentration of cisapride was increased by 81% (range, 38% to 138%; P < .01) and the total area under the plasma cisapride concentration-time curve by 144% (range, 65% to 244%; P < .01) by grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the grapefruit juice and control phases. CONCLUSIONS: Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in the small intestine. Concomitant use of high amounts of grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia.

Administration, Oral↗

PubMed1999

Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

OBJECTIVE: To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. RESULTS: Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. CONCLUSION: The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.

Administration, Oral↗

PubMed1999

The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron.

BACKGROUND: Ondansetron is an antiemetic agent metabolized by cytochrome P450 (CYP) enzymes. Rifampin (INN, rifampicin) is a potent inducer of CYP3A4 and some other CYP enzymes. We examined the possible effect of rifampin on the pharmacokinetics of orally and intravenously administered ondansetron. METHODS: In a randomized crossover study with 4 phases and a washout of 4 weeks, 10 healthy volunteers took either 600 mg rifampin (in 2 phases) or placebo (in 2 phases) once a day for 5 days. On day 6, 8 mg ondansetron was administered either orally (after rifampin and placebo) or intravenously (after rifampin and placebo). Ondansetron concentrations in plasma were measured up to 12 hours. RESULTS: The mean total area under the plasma concentration-time curve [AUC(0-infinity)] of orally administered ondansetron after rifampin pretreatment was reduced by 65% compared with placebo (P < .001). Rifampin decreased the peak plasma concentration of oral ondansetron by about 50% (from 27.2+/-3.0 to 13.8+/-1.5 ng/mL [mean +/- SEM]; P < .001]) and the elimination half-life (t1/2) by 38% (P < .01). The bioavailability of oral ondansetron was reduced from 60% to 40% (P < .01) by rifampin. The clearance of intravenous ondansetron was increased 83% (from 440+/-38.4 to 805+/-44.6 mL/min [P < .001]) by rifampin. Rifampin reduced the t1/2 of intravenously administered ondansetron by 46% (P < .001) and the AUC(0-infinity) by 48% (P < .001). CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of ondansetron after both oral and intravenous administration. The interaction is most likely the result of induction of the CYP3A4-mediated metabolism of ondansetron. Concomitant use of rifampin or other potent inducers of CYP3A4 with ondansetron may result in a reduced antiemetic effect, particularly after oral administration of ondansetron.

Administration, Oral↗

PubMed1999

Interaction between fluconazole and midazolam in intensive care patients.

BACKGROUND: Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism. METHODS: In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and alpha-hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter. RESULTS: Concentrations of midazolam were significantly increased (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of alpha-hydroxymidazolam to midazolam decreased progressively (P < 0.05). CONCLUSION: In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.

Adult↗

PubMed1999

Effect of activated charcoal alone or given after gastric lavage in reducing the absorption of diazepam, ibuprofen and citalopram.

AIMS: The efficacy of activated charcoal alone, and gastric lavage followed by charcoal in reducing the absorption of diazepam, ibuprofen and citalopram was studied in healthy volunteers. METHODS: In a randomized cross-over study with three phases, nine healthy volunteers were administered single oral doses of 5 mg diazepam, 400 mg ibuprofen and 20 mg citalopram, taken simultaneously after an overnight fast. Thirty minutes later, the subjects were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage followed by 25 g charcoal in suspension given through the lavage tube. Plasma concentrations of diazepam, ibuprofen and citalopram were determined up to 10 h. RESULTS: The AUC(0,10 h) of diazepam was reduced by 27% (P<0.05) by both charcoal alone and charcoal combined with lavage. The increase in plasma diazepam concentration from 0.5 h onwards was prevented by both interventions (P</=0.05), whereas the Cmax of diazepam was not significantly affected by either treatment. The AUC(0, 10 h) of ibuprofen was reduced by 49% (P<0.05) after the combination treatment and by 30% (P<0.05) after charcoal alone, but there was no significant difference between these two treatments. Both charcoal alone and the combination treatment were equally effective in preventing the increase in plasma ibuprofen from 0.5 h onwards (P<0.01). The Cmax of ibuprofen was reduced by 45% (P<0.05) and by 21% (P=NS), respectively. The AUC(0,10 h) of citalopram was reduced by 51% (P<0.05) after both charcoal alone and charcoal combined with lavage, and the Cmax by 52% (P<0.05) and 54% (P<0.05), respectively. The increase in plasma citalopram concentration from 0.5 h onwards was reduced by about 50% (P<0.01) by both interventions. CONCLUSIONS: Activated charcoal alone and charcoal combined with lavage showed similar efficacy in preventing the absorption of diazepam, ibuprofen and citalopram. These results suggest that gastric lavage needs not be routinely performed before administration of charcoal.

Adult↗

PubMed1999

Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.

BACKGROUND: Grapefruit juice greatly increases the bioavailability of lovastatin and simvastatin. We studied the effect of grapefruit juice on the pharmacokinetics of atorvastatin and pravastatin. METHODS: Two randomized, two-phase crossover studies were performed--study I with atorvastatin in 12 healthy volunteers and study II with pravastatin in 11 healthy volunteers. In both studies, volunteers took 200 mL double-strength grapefruit juice or water three times a day for 2 days. On day 3, each subject ingested a single 40 mg dose of atorvastatin (study I) or pravastatin (study II) with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours later. In addition, subjects took 200 mL grapefruit juice or water three times a day on days 4 and 5 in study I. In study I, serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid, 2-hydroxyatorvastatin lactone, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 72 hours. In study II, pravastatin, pravastatin lactone, and active and total HMG-CoA reductase inhibitors were measured up to 24 hours. RESULTS: Grapefruit juice increased the area under the serum concentration-time curve of atorvastatin acid from time zero to 72 hours [AUC(0-72)] 2.5-fold (P < .01), whereas the peak serum concentration (Cmax) was not significantly changed. The time of the peak concentration (tmax) and the elimination half-life (t1/2) of atorvastatin acid were increased (P < .01). The AUC(0-72) of atorvastatin lactone was increased 3.3-fold (P < .01) and the Cmax 2.6-fold (P < .01) by grapefruit juice, and the tmax and t1/2 were also increased (P < .05). Grapefruit juice decreased the Cmax (P < .001) and AUC(0-72) (P < .001) of 2-hydroxyatorvastatin acid and increased its tmax and t1/2 (P < .01). Grapefruit juice also decreased the Cmax (P < .001) and AUC(O-72) (P < .05) of 2-hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.3-fold (P < .05) and 1.5-fold (P < .01), respectively, by grapefruit juice. In study II, the only significant change observed in the pharmacokinetics of pravastatin was prolongation of the tmax of active HMG-CoA reductase inhibitors by grapefruit juice (P < .05). CONCLUSIONS: Grapefruit juice significantly increased serum concentrations of atorvastatin acid, atorvastatin lactone, and active and total HMG-CoA reductase inhibitors, probably by decreasing CYP3A4-mediated first-pass metabolism of atorvastatin in the small intestine. On the other hand, grapefruit juice had no effect on the pharmacokinetics of pravastatin. Concomitant use of atorvastatin and at least large amounts of grapefruit juice should be avoided, or the dose of atorvastatin should be reduced accordingly.

Adult↗

PubMed1999

Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors.

BACKGROUND: Vincristine is at least partly metabolized by CYP3A4. We have studied the possible effect of the CYP3A4-inducing antiepileptic agents carbamazepine and phenytoin on the pharmacokinetics of vincristine. METHODS: Fifteen adult patients with brain tumors receiving combination chemotherapy with procarbazine, lomustine, and vincristine volunteered for this open parallel-group study. Nine of the patients used either carbamazepine or phenytoin and six of the patients used no obvious CYP3A4-inducing medication. After intravenous infusion of 2 mg vincristine, timed blood samples were collected up to 24 hours. Plasma vincristine concentrations were measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of vincristine were compared between the two patient groups. RESULTS: The systemic clearance of vincristine was 63% higher (925 +/- 61 versus 569 +/- 76 mL/min [mean +/- SEM]; P = .004), the elimination half-life was 35% shorter (12.7 +/- 0.6 versus 19.4 +/- 3.6 hours; P = .13), and the total area under the plasma concentration-time curve was 43% smaller (37.3 +/- 2.4 versus 65.1 +/- 10.1 ng x h/mL; P = .04) in patients who were receiving carbamazepine or phenytoin than in the control group. CONCLUSIONS: Drugs that induce CYP3A4 can increase the elimination of vincristine. Further studies are needed to determine whether the increased clearance of vincristine by carbamazepine or phenytoin decreases the efficacy of vincristine.

Adult↗

PubMed1999

Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam.

BACKGROUND: The calcium channel blockers mibefradil and isradipine inhibit CYP3A4 in vitro. However, their in vivo inhibitory effects on CYP3A4 are not known in detail, although mibefradil was recently withdrawn from the market because of serious drug interactions. METHODS: The effects of mibefradil and isradipine on the pharmacokinetics and pharmacodynamics of oral triazolam, a model substrate of CYP3A4, were studied in a randomized, double-blind crossover study with three phases. Nine healthy subjects took 50 mg mibefradil, 5 mg isradipine, or placebo orally once a day for 3 days. On day 3, each subject received a single 0.25 mg oral dose of triazolam. Thereafter, blood samples were collected up to 18 hours, and pharmacodynamic effects of triazolam were measured up to 8 hours. RESULTS: Mibefradil increased the total area under the plasma triazolam concentration-time curve [AUC(0 - infinity)] 9-fold compared with placebo (P < .001). The peak plasma concentration of triazolam was increased 1.8-fold (3.4+/-0.1 ng/mL versus 1.8+/-0.2 ng/mL [mean +/- SEM]; P < .001), and the elimination half-life (t 1/2) was increased 4.9-fold (18.5+/-1.9 hours versus 4.0+/-0.5 hours; P < .001) by mibefradil. In addition, mibefradil was associated with increased pharmacodynamic effects of triazolam. In contrast to mibefradil, isradipine reduced the AUC(0 - infinity) and t 1/2 of triazolam by about 20% (P < .05) and had no significant effects on the pharmacodynamics of triazolam. CONCLUSION: Mibefradil but not isradipine markedly increases the plasma concentrations of triazolam and thereby enhances and prolongs its pharmacodynamic effects, consistent with potent inhibition of CYP3A4.

Administration, Oral↗

PubMed1999

Effect of itraconazole on the pharmacokinetics of bupivacaine enantiomers in healthy volunteers.

We studied seven healthy volunteers given itraconazole 200 mg orally or placebo, once daily for 4 days, in a crossover study. On day 4, racemic bupivacaine 0.3 mg kg-1 was given i.v. over 60 min and venous plasma samples were collected for 23 h. Plasma concentrations of R- and S-bupivacaine, itraconazole and hydroxyitraconazole were measured. Itraconazole reduced the clearance of R-bupivacaine by 21% (P < 0.05) and that of S-bupivacaine by 25% (P < 0.05), while it had no significant effect on other pharmacokinetic variables of the enantiomers. Reduction of bupivacaine clearance by itraconazole probably increases the steady-state concentration of bupivacaine enantiomers by 20-25%. This should be taken into account in the concomitant use of bupivacaine and itraconazole, although the interaction seems to be of limited clinical significance.

Adult↗

PubMed1999

Ritonavir's role in reducing fentanyl clearance and prolonging its half-life.

BACKGROUND: The human immunodeficiency virus protease inhibitor ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme, and ritonavir's concomitant administration with the substrates of this enzyme may lead to dangerous drug interactions. METHODS: The authors investigated possible interactions between ritonavir and intravenously administered fentanyl in a double-blind, placebo-controlled, cross-over study in two phases. Twelve healthy volunteers received orally ritonavir or placebo for 3 days; the dose of ritonavir was 200 mg three times on the first day and 300 mg three times on the second. The last dose of ritonavir 300 mg or placebo was given on the morning of the third day. On the second day, 2 h after the afternoon pretreatment dose, fentanyl 5 microg/kg was injected intravenously in 2 min with naloxone to moderate its effects, and 15 timed venous blood samples were collected for 18 h. RESULTS: Ritonavir reduced the clearance of fentanyl by 67% from 15.6+/-8.2 to 5.2+/-2.0 ml x min(-1) x kg(-1) (P<0.01). The area under the fentanyl plasma concentration-time curve from 0 to 18 h was increased from 4.8+/-2.7 to 8.8+/-2.3 ng x ml(-1) x h(-1) by ritonavir (P<0.01). Ritonavir did not affect the initial concentrations and the steady-state volume of distribution of fentanyl. One subject discontinued participation before fentanyl administration because of severe side effects, and during the study 8 of the remaining 11 subjects reported nausea. CONCLUSIONS: Ritonavir can inhibit the metabolism of fentanyl significantly, so caution should be exercised if fentanyl is given to patients receiving ritonavir medication.

Adult↗

PubMed1999

Determination of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) in human plasma by capillary gas chromatography.

Two separate gas chromatographic methods for the determination of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) in human plasma are described. Both procedures involve solid-phase extraction (the packing material of the cartridges used was C8 for buspirone and a mixed-mode sorbent for 1-PP), injection of the sample into a gas chromatograph equipped with a fused-silica capillary column and a nitrogen-phosphorus detector, and analysis with temperature programming (from 220 degrees C to 285 degrees C for buspirone and from 138 degrees C to 285 degrees C for 1-PP). The coating material of the analytical column was 5% diphenyl dimethyl silicone for buspirone and 50% diphenyl dimethyl silicone for 1-PP. Zolpidem was used as an internal standard in the buspirone assay and 1-phenylpiperazine in the 1-PP assay. Recovery of buspirone and 1-PP averaged 98% and 89%, respectively, and the limit of quantification was 0.2 ng/mL for both compounds. The between-run coefficients of variation ranged from 3.2% to 9.4% and from 2.9% to 8.6% for samples spiked with three different concentrations of buspirone and 1-PP, respectively. The suitability of these assays for pharmacokinetic studies was shown by analyzing timed plasma samples from volunteers after ingestion of a single therapeutic dose of buspirone (10 mg).

Anti-Anxiety Agents↗

PubMed1999

Midazolam alpha-hydroxylation by human liver microsomes in vitro: inhibition by calcium channel blockers, itraconazole and ketoconazole.

The inhibitory effects of five calcium channel blockers (diltiazem, isradipine, mibefradil, nifedipine and verapamil) and three azole antifungal agents (itraconazole, hydroxyitraconazole and ketoconazole) on the alpha-hydroxylation of midazolam, a probe drug for CYP3A4-mediated interactions in humans, were studied in vitro using human liver microsomes. IC50 and Ki values were determined for each inhibitor. The kinetics of the formation of alpha-hydroxymidazolam were best described by simple Michaelis-Menten kinetics. The estimated values of Vmax and Km were 696 pmol min.-(1) mg(-1) and 7.46 micromol l(-1), respectively. All the compounds studied inhibited midazolam alpha-hydroxylation activity in a concentration-dependent manner, but there were marked differences in their relative inhibitory potency. Ketoconazole was the most potent inhibitor of midazolam alpha-hydroxylation (IC50 0.12 micromol l (-1)), being 10 times more potent than itraconazole (IC50 1.2 micromol l(-1)). The inhibitory effect of hydroxyitraconazole (IC50 2.3 micromol l (-1) was almost as large as that of itraconazole. Among the calcium channel blockers, mibefradil was the most potent inhibitor of the alpha-hydroxylation of midazolam, with an IC50 value (1.6 micromol l (-1)) similar to that of itraconazole. The other calcium channel blockers were much weaker inhibitors than mibefradil: verapamil exhibited a modest inhibitory effect with an IC50 of 23 micromol l(-1), while isradipine, nifedipine and diltiazem, with IC50 values ranging from 57 to >100 micromol l (-1), were weak inhibitors. This rank order of potency against the alpha-hydroxylation Qf midazolam was verified by the Ki values. With the exception of diltiazem, these in vitro results conform with the observed interaction potential of these agents with midazolam and many other CYP3A4 substrates in vivo in man.

Antifungal Agents↗

PubMed1999

Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone.

The effects of inhibition and induction of the metabolism of buspirone on the plasma concentrations of 1-(2-pyrimidinyl)-piperazine (a piperazine metabolite), the principal active metabolite of buspirone, were investigated. Two separate randomized, placebo-controlled cross-over studies with two phases were carried out in healthy volunteers. In Study I, six subjects took itraconazole 200 mg daily or matched placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. In study II, six subjects took rifampicin 600 mg daily or matched placebo orally for 5 days. On day 6, 30 mg buspirone was administered orally. Buspirone and piperazine metabolite concentrations in plasma were determined by gas chromatography. Itraconazole decreased the mean AUC of the piperazine metabolite by 50% (P<0.05) and the Cmax by 57% (P<0.05) compared with placebo, whereas the mean AUC and Cmax of unchanged buspirone were increased 14.5-fold (P<0.05) and 10.5-fold (P<0.05), respectively, by itraconazole. Rifampicin had no significant effect on the AUC of the piperazine metabolite, but it increased the mean Cmax of the piperazine metabolite by 35% (P=0.08). The mean AUC and Cmax of parent buspirone were reduced by 91% (P<0.05) and 85% (P<0.05), respectively, by rifampicin. The mean ratio of the AUC of the piperazine metabolite to that of buspirone was decreased 34-fold (P<0.05) by itraconazole and increased 7.6-fold (P<0.05) by rifampicin. In conclusion, itraconazole and rifampicin caused only relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although they had drastic effects on the concentrations of parent buspirone.

Adolescent↗

PubMed1999

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

Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(0-infinity)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P<0.01) and AUC(0-infinity) by 60% (P<0.01). The clinical implication of this study is that erythromycin and itraconazole may significantly increase the plasma concentrations and toxicity of oral lignocaine. The extent of the interaction of lignocaine with these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency of erythromycin and itraconazole.

Administration, Oral↗