Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline

Abstract

Aims Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline. Methods Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double-blind, four-period, placebo-controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8-10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady-state (day 10). Results In all periods, point estimates and 90% confidence intervals of the area under the concentration-time curves (AUC), maximum steady-state concentrations and peak-trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87-0.97), 0.90 (0.85-0.95) and 1.00 (0.95-1.06) for omeprazole, lansoprazole and pantoprazole, respectively. Conclusions Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline.Keywords: cytochrome P4501A2, drug interaction, proton pump inhibitors, theophylline isoenzymes of cytochrome P450 [6][7][8][9][10][11]. For example, Introduction omeprazole and lansoprazole were shown to be inducers of cytochrome P4501 A2 (CYP1A2) in human liver and The H + , K + -ATPase ( proton pump) inhibitors (PPI) omeprazole, lansoprazole and pantoprazole have been alimentary tract in vitro and in vivo [12][13][14]. The extent of CYP1A2 induction by omeprazole was dependent proved effective as monotherapy for gastric or duodenal ulcers and gastro-oesophageal reflux, and in combination both on the dose and the CYP2C19 phenotype resulting in a significant effect at lower doses of omeprazole in regimens for the eradication of Helicobacter pylori [1][2][3]. These drugs are structurally very similar and they are the subset of poor metabolisers of CYP2C19 [15]. Pantoprazole has been claimed to have less potential than mainly metabolized by the polymorphically expressed cytochrome P4502C19 (CYP2C19), which means that omeprazole and lansoprazole to interact with other drugs metabolized by cytochrome P450 enzymes [16, 17]. In about 3% of Caucasians ( poor metabolisers of CYP2C19) eliminate the compounds more slowly than the majority general, putative induction of CYP1A2 by PPI in vivo is highly controversial as clinical studies have shown that (extensive metabolisers of CYP2C19) of the Caucasian population [4,5]. As a class, be...

Expression and Induction Potential of Cytochromes P450 in Human Cryopreserved Hepatocytes

“…In addition, these human hepatocyte cultures have proven also to be a reliable in vitro model for evaluating NCEs as inducers of P450s (Kostrubsky et al, 1999;LeCluyse et al, 2000;Silva and Nicoll-Griffith, 2002). When in vitro P450 induction experiments are conducted at therapeutically relevant concentrations of the NCEs, in most cases, the in vitro data correlate well with clinical observations (Dilger et al, 1999;LeCluyse et al, 2000;Madan et al, 2003).…”

Predictors of the clinical effects of pirfenidone on idiopathic pulmonary fibrosis

“…Thus, omeprazole and lansoprazole may accelerate pirfenidone metabolism and theoretically decrease its serum concentration and clinical effects; however, in vitro studies are not always consistent with in vivo studies. In vivo interactions of theophylline and caffeine, which are metabolized by CYP1A2, with omeprazole could be clinically negligible in accordance to pharmacokinetic studies [29]. Although the coadministration of pirfenidone and PPIs might not affect the in vivo clinical effects, rabeprazole is better than omeprazole and lansoprazole from the standpoint of CYP1A2 induction.…”

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

“…When hepatocytes are cultured using appropriate conditions which facilitate liver-like cell morphology and expression of liver-specific proteins, CYP enzymes are effectively induced in vitro analogous to the in vivo situation in terms of the magnitude and specificity of induction (37,38). For example, omeprazole is an effective in vitro inducer of human CYP1A2 (37,39), but the EC 50 of omeprazole induction is much larger than the typical exposure in humans treated for gastric ulcers, thus it rarely causes significant clinical drug interactions because the concentration of omeprazole required to induce CYP1A2 exceeds the concentrations achieved in vivo (37,40,41). In addition to CYP enzymes, numerous studies have been reported using primary hepatocyte culture systems to assess induction of a variety of gene targets from Phase II enzymes and transporters (42)(43)(44)(45).…”