The pharmacokinetics, pharmacodynamics and safety of oral doses of ilaprazole 10, 20 and 40 mg and esomeprazole 40 mg in healthy subjects: a randomised, open-label crossover study.

BACKGROUND: Ilaprazole, a proton pump inhibitor (PPI) currently in clinical use, may provide improved acid suppression vs. other PPIs. AIM: To compare the pharmacodynamic and pharmacokinetic profiles of ilaprazole and esomeprazole. METHODS: A phase 1, randomised, open-label, single-centre, 4-period crossover study was conducted in 40 healthy volunteers. Ilaprazole 10, 20 or 40 mg or esomeprazole 40 mg was administered once daily for 5 days with ≥5-day washout intervals. Pharmacokinetic blood samples and intragastric pH measurements were collected at scheduled timepoints for 24 h after dosing on Days 1 and 5. RESULTS: Esomeprazole 40 mg provided significantly better pH control during the initial hours (0-4 h) after a single dose, but ilaprazole (particularly 20 and 40 mg) provided significantly better pH control for the entire 24-h period and during evening and overnight hours after single and multiple doses. Increasing ilaprazole doses resulted in dose-proportional increases in peak plasma concentration and area under the plasma concentration vs. time curve following single and multiple doses. Ilaprazole was safe and generally well tolerated; an unexpectedly high incidence of allergic eye and skin reactions were observed but were not specific to any dosing regimen. Plasma gastrin concentrations did not increase proportionately with increasing ilaprazole dose. CONCLUSIONS: Ilaprazole provided significantly better pH control over 24 h and during evening and overnight hours compared with esomeprazole in healthy volunteers, which may translate to greater relief of night-time heartburn in the clinical setting for patients with gastric acid-related disorders.

Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h.

BACKGROUND: Attainment of intragastric pH < 6.0 may require high-dose continuously infused proton pump therapy. AIM: To assess the pharmacokinetic and pharmacodynamic dose-responses of continuous infusion regimens of lansoprazole. METHODS: Healthy adult subjects were assigned to lansoprazole 60-mg intravenous bolus, followed by 6-mg/h continuous infusion; a 90-mg intravenous bolus followed by 6-, 7.5-, or 9-mg/h continuous infusion; or placebo. RESULTS: Mean intragastric pH values for lansoprazole regimens ranged from 4.8 to 5.2 (0-24 h), 5.5 to 6.0 (>24 to 48 h) and 5.2 to 5.6 (0-48 h). Within these three intervals, the percentages of time intragastric pH exceeded 4, 5 and 6 ranged from 65% to 96%, 54% to 88% and 30% to 61% respectively. Pharmacokinetic parameters were dose-independent with steady-state plasma concentrations achieved within 6-12 h postdose and maintained over 48 h. The mean systemic clearance of lansoprazole was lower in CYP2C19 heterozygous metabolizers than in homozygous extensive metabolizers (9.2 vs. 16.5 L/h), with substantial variability resulting in overlapping ranges of clearance values for both subpopulations. All lansoprazole regimens were well-tolerated. CONCLUSIONS: Lansoprazole administered as a 60-mg intravenous bolus followed by 6-mg/h continuous infusion produced intragastric pH effects comparable with those of higher dosage regimens.

Lansoprazole regimens that sustain intragastric pH > 6.0: an evaluation of intermittent oral and continuous intravenous infusion dosages.

BACKGROUND: Orally and intravenously administered proton pump inhibitors have been shown to reduce rebleeding rates, surgery and transfusion requirement. AIM: To compare lansoprazole intravenous and orally disintegrating tablet (Prevacid SoluTab) regimens with a pantoprazole intravenously administered regimen in sustaining intragastric pH >6.0. METHODS: Two similarly designed three-way, randomized crossover studies each enrolled 36 Helicobacter pylori-negative healthy volunteers. Study 1 regimens included intravenously administered bolus followed by 24-h continuous infusion (lansoprazole 90 mg, 6 mg/h; lansoprazole 120 mg, 6 mg/h; pantoprazole 80 mg, 8 mg/h). Study 2 regimens included intravenous bolus followed by lansoprazole orally disintegrating tablet or intravenous continuous infusion for 24 h (lansoprazole 90 mg, lansoprazole orally disintegrating tablet 60 mg every 6 h; lansoprazole 120 mg, 9 mg/h; pantoprazole 80 mg, 8 mg/h). Percentage of time pH >6.0 was assessed with 24-h intragastric pH monitoring. RESULTS: All regimens produced comparable gastric acid suppression. In both studies, regimens superior to pantoprazole included lansoprazole 90 mg, 6-mg/h; lansoprazole 90 mg, lansoprazole orally disintegrating tablet 60 mg q.d.s. and lansoprazole 120 mg, 9 mg/h (P < or = 0.013). The lansoprazole 120-mg, 6-mg/h regimen (P = 0.082) was not superior to pantoprazole in percentage of time intragastric pH >6.0. Mild reaction at the intravenous injection site was the most frequently reported adverse event. CONCLUSIONS: The intravenous bolus and continuously infused lansoprazole or intravenous bolus and intermittent lansoprazole orally disintegrating tablet regimens are as effective as intravenous pantoprazole in sustaining intragastric pH >6.0.

A novel option in proton pump inhibitor dosing: lansoprazole orally disintegrating tablet dispersed in water and administered via nasogastric tube.

BACKGROUND: Lansoprazole orally disintegrating tablet, which rapidly disintegrates on the tongue or in water, provides a dosing alternative for patients with difficulty in swallowing. Gastric and nasogastric tubes are increasingly placed in patients with more severe swallowing disorders. AIM: This study assessed the pharmacokinetic profile of lansoprazole orally disintegrating tablet dispersed in a small volume of water and administered through a small-bore nasogastric tube. METHODS: Forty healthy adult men and women (18-43 years) received two single 30 mg lansoprazole orally disintegrating tablet doses (one administered directly onto the tongue without water, and one dispersed in water and administered via nasogastric tube) in a randomized, crossover fashion. RESULTS: The total plasma exposure to lansoprazole was comparable following both dosing regimens; mean AUC values for the lansoprazole orally disintegrating tablet nasogastric dispersion were < or =8.6% greater than those for the intact lansoprazole orally disintegrating tablet. Lansoprazole Cmax for the lansoprazole orally disintegrating tablet nasogastric dispersion was 20.9% greater than that for the intact lansoprazole orally disintegrating tablet, a difference of no clinical significance. CONCLUSIONS: Dispersion of the lansoprazole orally disintegrating tablet in a small volume of water and administering via nasogastric tube does not reduce the pharmacokinetic profile of the intact lansoprazole orally disintegrating tablet. This alternative dosing method may be useful in patients with nasogastric or gastric tubes.

A novel option for dosing of proton pump inhibitors: dispersion of lansoprazole orally disintegrating tablet in water via oral syringe.

BACKGROUND: A new formulation of lansoprazole, the lansoprazole orally disintegrating tablet, rapidly disintegrates in water eliminating the need for swallowing whole pills. AIM: To assess the effect that dispersing the lansoprazole orally disintegrating tablet in water would have on lansoprazole pharmacokinetics. METHODS: Forty healthy adult men and women (18-43 years) received two single 15 mg lansoprazole orally disintegrating tablet doses separated by 3 days (one administered directly onto the tongue without water and one dispersed in water and administered orally via syringe) in a randomized, crossover fashion. Serial plasma samples were determined from 0 to 12 h for each dose. Ratios of central values for peak plasma exposure (C(max)) and mean overall extent of exposure (area under the plasma concentration) were used to compare the bioavailability. RESULTS: The two dosing regimens were bioequivalent, with the point estimate for area under the plasma concentration equalling 1.080 (confidence interval 1.012-1.152) and the point estimate for C(max) equalling 1.082 (confidence interval 0.961-1.218). CONCLUSIONS: Dispersing the 15 mg lansoprazole orally disintegrating tablet in water and administering the dose orally via syringe is bioequivalent to the 15 mg intact lansoprazole orally disintegrating tablet with respect to lansoprazole area under the plasma concentration and C(max). This dosing route provides an additional, convenient dosing option for lansoprazole.

Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir.

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.

[O-methyl 14C]naproxen O-demethylase activity in human liver microsomes: evidence for the involvement of cytochrome P4501A2 and P4502C9/10.

Cytochrome P450 (CYP) activity in human liver microsomes was measured after the O-demethylation of [O-methyl 14C]naproxen (NAPase). The formation of [14C]formaldehyde in the presence of microsomes was described by an apparent KM(1) and Vmax(1) of 0.16 +/- 0.09 mM and 4.1 +/- 2.8 nmol HCHO/min/mg protein (mean +/- SD; N = 5 different livers), respectively, over a relatively wide naproxen concentration (5-1600 microM) range. With two sets of microsomes, a high KM NAPase component was also detected (mean KM2 = 2.7 mM; mean Vmax2 = 23 nmol HCHO/min/mg). As expected, the O-demethylation of naproxen (0.4 mM) was found to be highly correlated with tolbutamide hydroxylase (TOLase) activity in a panel of human liver microsomes (r = 0.82, p < 0.01, N = 10) and was inhibited (32-54%) by a number of purported CYP2C (CYP2C9/10) inhibitors/substrates (e.g. phenytoin, sulfaphenazole, tienilic acid, tolbutamide, and ibuprofen). Only marginal decreases in activity (< or = 14%) were observed with inhibitors of other CYP proteins. However, NAPase activity was also found to correlate significantly with CYP1A2 [ethoxyresorufin O-deethylase (ERODase)] activity (r = 0.68, p < 0.05, n = 11). In addition, the reaction was inhibited (36-75%, N = 11 different livers) by furafylline (FURA), a CYP1A2-selective mechanism-based inhibitor. The effect of FURA and tienilic acid was additive, leading to 90 +/- 4.2% inhibition of NAPase activity. FURA-inhibited activity also significantly correlated with ERODase activity (r = 0.78, p < 0.01, N = 11), whereas tienilic acid-inhibited activity correlated with TOLase activity (r = 0.63, p < 0.05, N = 10). In human B-lymphoblast microsomes, cDNA-expressed CYP1A2 exhibited relatively high activity (KM = 0.25 mM; Vmax = 24 nmol/min/nmol CYP), when compared with CYP2A6, CYP2D6, CYP2E1, CYP2B6, and CYP3A4. The kinetic parameters for reconstituted purified human liver microsomal CYP2C9 (KM = 0.43 mM; Vmax = 11 nmol/min/nmol CYP) were comparable with those of CYP1A2. It is concluded that the O-demethylation of naproxen (< or = 0.4 mM) is catalyzed by CYP2C subfamily members (CYP2C9/10) and CYP1A2 in human liver microsomes.

In vitro hepatic metabolism of ABT-418 in chimpanzee (Pan troglodytes). A unique pattern of microsomal flavin-containing monooxygenase-dependent stereoselective N'-oxidation.

Metabolism of the cholinergic channel activator [N-methyl-3H]ABT-418 was studied using precision-cut tissue slices and microsomes (+/- cytosol) prepared from a single chimpanzee liver. In both cases, the products of C-oxidation (lactam) and N'-oxidation (cis > trans) were detected. In the presence of chimpanzee liver microsomes and cytosol, which had been characterized with respect to the levels of aldehyde oxidase (N1-methylnicotinamide oxidase), NADPH-dependent flavin-containing monooxygenase (FMO; N, N-dimethylaniline N-oxidase), and various cytochrome P450 (CYP)-dependent monooxygenase activities, ABT-418 lactam and N'-oxide formation was found to be largely dependent on CYP/aldehyde oxidase and FMO, respectively. The rank order of total (trans + cis) FMO-dependent N'-oxidation in liver microsomes was dog > rat > rabbit > chimpanzee > or = cynomolgus monkey > human. It is concluded that the metabolic profile of ABT-418 in the chimpanzee is unique. First, the C-/N'-oxidation ratio in liver slices (0.43) is similar to that of the rat and dog and dissimilar to that of the rat and dog and dissimilar to that of the two other primate species studied; human and cynomolgus monkey (C-/N'-oxidation ratio > or = 9.4). Second, the pattern of ABT-418 N'-oxidation observed with chimpanzee liver microsomes, and liver slices (trans:cis = 1:3), differs from that of rat, rabbit, and dog liver microsomes, rat and human kidney S-9 (trans >> cis), human liver microsomes (trans:cis approximately 1:1), and cynomolgus monkey (trans:cis approximately 2:1) liver microsomes. Lack of stereoselective N'-oxidation by human FMO was confirmed with cDNA-expressed FMO3.

In vitro metabolism of terfenadine by a purified recombinant fusion protein containing cytochrome P4503A4 and NADPH-P450 reductase. Comparison to human liver microsomes and precision-cut liver tissue slices.

The metabolism of terfenadine was studied with a cDNA-expressed/purified recombinant fusion protein containing human liver microsomal cytochrome P4503A4 (CYP3A4) linked to rat NADPH-P450 reductase (rF450[mHum3A4/mRatOR]L1) and was compared with that observed in the presence of human liver microsomes and precision-cut human liver tissue slices. In all three cases, [3H]terfenadine was metabolized to at least three major metabolites. LC/MS (electrospray) analysis confirmed that these metabolites were alpha, alpha-diphenyl-4-piperidinomethanol (M5), t-butyl hydroxy terfenadine (M4), and t-butyl carboxy terfenadine (M3), although the level of M5 detected in the presence of fusion protein was greater than that found with microsomes or tissue slices. Two additional metabolites, M1 (microsomes and tissue slices) and M2 (fusion protein), were also detected, but remain uncharacterized. Consumption of parent drug (microsomes: KM = 9.58 +/- 2.79 microM, Vmax = 801 +/- 78.3 pmol/min/nmol CYP; fusion protein: KM = 14.1 +/- 1.13 microM, Vmax = 1670 +/- 170 pmol/min/nmol CYP) and t-butyl hydroxylation to M4 (microsomes: KM = 12.9 +/-3.74 microM, Vmax = 643 +/- 62.5 pmol/min/nmol CYP, ; fusion protein: KM = 30.0 +/- 2.55 microM, Vmax = 1050 +/- 141 pmol/min/nmol CYP) obeyed Michaelis-Menten kinetics over the terfenadine concentration range of 1-200 microM. Ketoconazole, a well-documented CYP3A inhibitor, effectively inhibited terfenadine metabolism in all three models. The conversion of M4 to M3, studied with human liver microsomes and fusion protein, was NADPH-dependent and inhibited by ketoconazole. It is concluded that cDNA-expressed CYP3A4, in the form of a NADPH-P450 reductase-linked fusion protein, may also serve as a model for studying the metabolism of terfenadine in vitro and many other drugs.

In vitro plasma protein binding of zileuton and its N-dehydroxylated metabolite.

An ultrafiltration technique or equilibrium dialysis has been used to study the in vitro human plasma protein binding of racemic zileuton, its individual enantiomers, and its pharmacologically inactive metabolite N-dehydroxyzileuton. The plasma protein binding of zileuton and N-dehydroxyzileuton over the concentration range of 0.1 to 100 mg/L averaged 93.1 +/- 0.22 and 92.0 +/- 0.12%, respectively. However, there appeared to be a stereoselective effect, with the R(+) enantiomer of zileuton demonstrating greater binding to plasma proteins than the S(-) enantiomer (96 vs 88%, respectively). Zileuton was bound to both human serum albumin (40 g/L) and alpha 1-acid glycoprotein (1 g/L), although binding affinity to albumin was approximately 3-fold greater. Displacement interactions of zileuton with warfarin, salicylate, theophylline, naproxen, ibuprofen, prednisone, and terfenadine were minimal. The blood to plasma concentration ratio for zileuton and N-dehydroxyzileuton ranged from 0.65 to 0.68, indicating that these compounds were mainly distributed in the plasma. Thus, zileuton is approximately 93% bound to plasma proteins at expected therapeutic concentrations in vitro, and this figure is largely unaffected by several commonly prescribed agents with which the drug may be coadministered.

Measurement of liver microsomal cytochrome p450 (CYP2D6) activity using [O-methyl-14C]dextromethorphan.

The activity of human liver microsomal cytochrome P4502D6 (CYP2D6) is readily estimated by following the O-demethylation of [O-methyl-14C]dextromethorphan. The basis of the assay is the quantitative measurement of [14C]formaldehyde (0.05-4.0 microM) after addition of NaOH to the microsomal incubates and extraction with methylene chloride. The assay is relatively simple, sensitive (limit of detection is approximately 5.0 pmol HCHO/h/mg microsomal protein) and does not require the use of HPLC or an internal standard. Formation of radiolabeled formaldehyde in human liver microsomes is linear for 20 min, up to a final protein concentration of 1.0 mg/ml. Furthermore, the O-demethylase activity in a panel of microsomes prepared from a series of human livers was significantly correlated with the immunochemically determined levels of CYP2D6 protein (r = 0.925, p < 0.001), and was inhibited (> 89%) by quinidine and lobeline. In addition, [O-methyl-14C]-dextromethorphan O-demethylation was exclusively catalyzed by cDNA-expressed CYP2D6 in microsomes prepared from human B-lymphoblast cells. The method is suitable for rapid screening of compounds as potential CYP2D6 cosubstrates and/or inhibitors.