Influence of Different Proton Pump Inhibitors on Activity of Cytochrome P450 Assessed by [¹³C]‐Aminopyrine Breath Test

Abstract

Aminopyrine is metabolized by cytochrome P450 (CYP) in the liver. The investigators evaluated influences of different PPIs on CYP activity as assessed by the [(13)C]-aminopyrine breath test ([(13)C]-ABT). Subjects were 15 healthy volunteers with different CYP2C19 status (5 rapid metabolizers [RMs], 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]). Breath samples were collected before and every 15 to 30 minutes for 3 hours after oral ingestion of [(13)C]-aminopyrine 100 mg on day 8 of each of the following regimens: control; omeprazole 20 mg and 80 mg, lansoprazole 30 mg, and rabeprazole 20 mg. Changes in carbon isotope ratios in carbon dioxide ((13)CO(2)/(12)CO(2)) in breath samples were measured by infrared spectrometry and expressed as delta-over-baseline (DOB) ratios (‰). Mean areas under the curve of DOB from 0 to 3 h (AUC(0-3h) of DOB) were significantly decreased by omeprazole 20 mg and lansoprazole 30 mg but not by rabeprazole 20 mg. Conversely, higher PPI dose (ie, omeprazole 80 mg) seemed to further decrease AUC(0-3h) of DOB in RMs but increased it in PMs. Omeprazole and lansoprazole at the standard doses inhibit CYP activity but rabeprazole does not, whereas high-dose omeprazole seems to induce CYPs.

Randomised clinical trial: prevention of recurrence of peptic ulcers by rabeprazole in patients taking low‐dose aspirin

“…Under these circumstances, PPIs with fewer drug interactions would be preferred, because the drug interaction may induce adverse effects or decrease the efficacy of the concomitantly administered drug by increasing or decreasing its plasma concentration, respectively. A recent study of the effects of PPIs on cytochrome 450 (CYP) activity assessed by the [ 13 C]‐aminopyrene breath test in healthy subjects showed that omeprazole and lansoprazole at the standard doses inhibit CYP activity, while rabeprazole does not . This finding is consistent with the previously known fact that rabeprazole has relatively less effects on CYP2C19 and CYP3A4 .…”

“…Appropriate selection of the concomitant PPI is an important issue in elderly LDA users. Rabeprazole is less affected by CYP2C19 genotype, and has little interaction with clopidogrel, which is often used together with LDA . It is also reported to be safe even if used concomitantly with warfarin after open‐heart surgery, as it is unlikely to produce haemorrhagic complications .…”

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…The N-demethylation of aminopyrine, the first probe drug used in breath tests, is mediated by several CYP450 enzymes, with CYP2C19 being the most important isoform [122]. Kodaira et al found a significant correlation between AUC 0-3h of DOB 13 CO 2 / 12 CO 2 ratios and both plasma [ 13 C]-aminopyrine AUC 0-3h and clearance [123]. [ 13 C]-pantoprazole has been proposed as an alternative CYP2C19 phenotyping probe, as several studies found significantly lower DOB values in CYP2C19 poor metabolizers compared to intermediate or extensive metabolizers [124][125][126][127][128][129].…”

Critical appraisal of 13C breath tests for microsomal liver function: aminopyrine revisited

“…13 C-labelled microsomal breath tests values can further be influenced by both endogenous and exogenous factors that may affect the activity of the cytochrome P450 enzymes, such as genetic polymorphisms and drugs respectively. A recent study in 15 healthy volunteers for example showed the influence of polymorphisms in the CYP2C19 gene on the 13 C 2 -aminopyrine breath test, reporting lower values in PMs for CYP2C19 than in IMs and rapid metabolizers (RMs) (49). Although low 13 C 2 -aminopyrine breath test values can thus be the consequence of polymorphisms in the CYP2C19 gene that results into a PM phenotype, this phenotype is only present in 2-6% of Caucasians (50) and thereby would not be a major confounding factor in routine clinical practice.…”