Jouko Laitila

Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate

Concomitant use of fibrates with statins has been associated with an increased risk of myopathy, but the underlying mechanism of this adverse reaction remains unclear. Our aim was to study the effects of bezafibrate and gemfibrozil on the pharmacokinetics of lovastatin.

Cyclosporine markedly raises the plasma concentrations of repaglinide

Repaglinide is an antidiabetic drug metabolized by cytochrome P450 (CYP) 2C8 and 3A4, and it appears to be a substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1). We studied the effects of cyclosporine (INN, ciclosporin), an inhibitor of CYP3A4 and OATP1B1, on the pharmacokinetics and pharmacodynamics of repaglinide.

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol

Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the β‐adrenergic receptor‐blocking agent celiprolol in healthy volunteers.

Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations

Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol‐lowering drug simvastatin has an extensive first‐pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin.

The Effect of Gemfibrozil on Repaglinide Pharmacokinetics Persists for at Least 12 h After the Dose: Evidence for Mechanism‐based Inhibition of CYP2C8 In Vivo

Repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and 3A4. Gemfibrozil has the effect of increasing the area under the concentration–time curve (AUC) of repaglinide eightfold. We studied the effect of dosing interval on the extent of the gemfibrozil–repaglinide interaction. In a randomized five‐phase crossover study, 10 healthy volunteers ingested 0.25 mg repaglinide, with or without gemfibrozil pretreatment. Plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. When the last dose of 600 mg gemfibrozil was ingested simultaneously with repaglinide, or 3, 6, or 12 h before, it increased the AUC0–∞ of repaglinide 7.0‐, 6.5‐, 6.2‐ and 5.0‐fold, respectively (P < 0.001). The peak repaglinide concentration increased approximately twofold (P < 0.001), and the half‐life was prolonged from 1.2 h to 2–3 h (P < 0.001) during all the gemfibrozil phases. The drug interaction effects persisted at least 12 h after gemfibrozil was administered, although plasma gemfibrozil and gemfibrozil 1‐O‐β‐glucuronide concentrations were only 5 and 10% of their peak values, respectively. The long‐lasting interaction is likely caused by mechanism‐based inhibition of CYP2C8 by gemfibrozil glucuronide.

High performance liquid chromatography–tandem mass spectrometry for the determination of bile acid concentrations in human plasma

We report a sensitive and robust method to determine cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and their taurine- and glycine-conjugate concentrations in human plasma using liquid chromatography-tandem mass spectrometry. Activated charcoal was utilized to prepare bile acid-free plasma, which served as the biological matrix for the preparation of standard and quality control samples. Plasma sample preparation involved solid-phase extraction. A total of 16 bile acids and 5 internal standards were separated on a reverse column by gradient elution and detected by tandem mass spectrometry in negative ion mode. The calibration curve was linear for all the bile acids over a range of 0.005-5micromol/L. The extraction recoveries for all the analytes fell in the range of 88-101%. Intra-day and inter-day coefficients of variation were all below 10%. A stability test showed that all the bile acids were stable in plasma for at least 6h at room temperature, at least three freeze-thaw cycles, in the -70 degrees C or -20 degrees C freezer for 2 months, and also in the reconstitution solution at 8 degrees C for 48h. Comparison of the matrix effect of bile acid-free plasma with that of real plasma indicated that the charcoal purification procedure did not affect the properties of charcoal-purified plasma as calibration matrix. This method has been used to determine the bile acid concentrations in more than 300 plasma samples from healthy individuals. In conclusion, this method is suitable for the simultaneous quantification of individual bile acids in human plasma.

Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2

Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with tizanidine.

Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride

Our objective was to study the effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug.

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

AbstractBackground: 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.

Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast.

According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration–time curve (AUC)0–∞, peak plasma concentration (Cmax), and elimination half‐life (t1/2) of montelukast 4.5‐fold, 1.5‐fold, and 3.0‐fold, respectively (P < 0.001). After administration of gemfibrozil, the time to reach Cmax (tmax) of the montelukast metabolite M6 was prolonged threefold (P = 0.005), its AUC0–7 was reduced by 40% (P = 0.027), and the AUC0–24 of the secondary metabolite M4 was reduced by >90% (P < 0.001). In human liver microsomes, gemfibrozil 1‐O‐β glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35‐fold more potently than did gemfibrozil (half‐maximal inhibitory concentration (IC50) 3.0 and 107 µmol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.