Quinidine single dose pharmacokinetics and pharmacodynamics are unaltered by omeprazole

Abstract

Omeprazole has been shown in previous studies to inhibit the hepatic metabolism of selected drugs. Quinidine is an antiarrhythmic and antimalarial agent with a low therapeutic index. We therefore examined the effect of 40 mg omeprazole daily for one week or placebo on the pharmacokinetics and pharmacodynamics of a single 400 mg dose of quinidine in 8 healthy volunteers in a double-blind crossover study.During placebo and omeprazole treatment, there was no significant difference in area under the time-plasma quinidine concentration curve, (17.0 f 4.83 p g . h/ml, 18.6 k 4.43 pg . h/ml, respectively; P > 0.2) or renal clearance of quinidine (56.2 respectively; P > 0.5). Quinidine unbound fraction in plasma (0.170f0.041 US. 0.166k0.041 in the presence of omeprazole; P > 0.5) was not altered by omeprazole. Peak plasma quinidine concentration and the time this occurred did not differ. Omeprazole also had no effect on these parameters for the metabolite 3-hydroxyquinidine. There was no significant difference in the change in the corrected Q-T interval on the electrocardiogram due to quinidine (mean area under the time versus 26.0 ml/min, 55.6 -t 12.7 ml/min,

Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans

“…The weak response in CYP3A4 mRNA by phenytoin in spite of known induction properties in vivo may be explained by the concentration used in vitro (10 mM), which is below the concentration (40Y80 mM) reported to cause induction in vivo (31). Omeprazole significantly induced CYP3A4 mRNA in the liver slices but is not reported to be an in vivo inducer (32). However, as for CYP1A induction, this can be explained by the supratherapeutic concentrations used in the study.…”

Physiologically‐based pharmacokinetic modeling of quinidine to establish a CYP3A4, P‐gp, and CYP2D6 drug–drug–gene interaction network

“…(a–f) Predicted compared to observed plasma concentration‐time profiles of quinidine and 3‐hydroxyquinidine alone and after pretreatment with and/or concomitant administration of (a) carbamazepine, (b) fluvoxamine, (c) itraconazole, (d) R‐/S‐omeprazole, (e) rifampicin, and (f) R‐/S‐verapamil (low verapamil dose regimen). Population geometric means are shown as lines (solid: quinidine and 3‐hydroxyquinidinde alone, dashed: quinidine and 3‐hydroxyquinidinde during DDI), geometric standard deviations are shown as shaded areas and observed data are shown as dots (control) and squares (DDI) (±standard deviation, if reported) 26,32–36 . Quinidine doses indicate quinidine sulfate administration.…”

“…(a, b) For quinidine acting as a cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) victim, predicted drug−drug interaction (DDI) (a) area under the plasma concentration-time curve calculated between the first and last concentration measurement (AUC last ) and (b) maximum plasma concentration (C max ) ratios of quinidine and 3-hydroxyquinidine are plotted against their respective observed values after pretreatment with and/or concomitant administration of carbamazepine, cimetidine, fluvoxamine, itraconazole, R-/S-omeprazole, rifampicin, and R-/S-verapamil. 26,[32][33][34][35][36]43,44 (c, d) For quinidine acting as a CYP2D6 and P-gp perpetrator, predicted DD(G)I (c) AUC last and (d) C max ratios of dextromethorphan (DEX), dextrorphan-O-glucuronide (DXG), total dextrorphan (DTT), digoxin (DIG), metoprolol (MET), S-metoprolol (SME), and R-metoprolol (RME), mexiletine (MEX) and paroxetine (PAR) are plotted against their respective observed values after pretreatment with and/or concomitant administration of quinidine. 11,[37][38][39][40][41][42]45 The solid line represents the line of identity, whereas 1.25-fold and two-fold prediction limits are shown as dotted and dashed lines, respectively.…”

“…(a-f) Predicted compared to observed plasma concentration-time profiles of quinidine and 3-hydroxyquinidine after (a) intravenous and (b-f) oral administration. Population geometric means are shown as lines, geometric standard deviations are shown as shaded areas, and observed data are shown as dots (training dataset) and triangles (test dataset) (±standard deviation, if reported) 8,[25][26][27][28][29]. (g-i) Goodness-of-fit plots comparing predicted and observed (g) plasma concentrations, (h) area under the plasma concentration-time curve calculated between first and last concentration measurement (AUC last ) and (i) maximum plasma concentration (C max ) values.…”

In vitro to human in vivo translation – pharmacokinetics and pharmacodynamics of quinidine

“…the study inclusion criteria were: a) healthy Caucasian volunteers, b) availability of information about the quinidine pharmacokinetics, ideally presented as a drug plasma concentration change in time, c) PD results presented as Qt/ QTc or ΔQT/ΔQTc (regardless of the correction type), thus comparable with the simulation outputs. Nine papers fulfilling such conditions were identified and used for the study (Belz et al, 1982;Ching et al, 1991;El-Eraky and Thomas, 2003;Fieldman et al, 1977;Kaukonen et al, 1997;laganiere et al, 1996;Min et al, 1996;Olatunde and Price Evans, 1982;Shin et al, 2007). Characteristics of the clinical studies derived from the identified papers are presented in Table 1.…”