Effect of co-administered inducer or inhibitor on omeprazole pharmacokinetics based on CYP2C19 genotype.

Polymorphisms of cytochrome P450 (CYP) enzymes can affect enzymatic activity, drug metabolism and drug interactions. Although the potential for drug interactions is especially important when co-administering drugs with strong inductive or inhibitory potential towards drug-metabolizing enzymes, the relationship between CYP genotypes and the extent of the inductive or inhibitory effects remain poorly understood. We investigated the effects of rifampicin (inductive) and fluvoxamine (inhibitory) on metabolism of omeprazole and CYP2C19 enzymatic activity in 19 healthy Japanese subjects. Pharmacokinetic analyses of the CYP2C19 probe drug, omeprazole, were performed before and after rifampicin or fluvoxamine administration. The allele frequencies of the CYP2C19*1, CYP2C19*2 and CYP2C19*3 genotypes were 65.8%, 26.3% and 7.9%, respectively. Subjects with the CYP2C19*1 allele displayed higher levels of omeprazole metabolism than those without the CYP2C19*1 allele. Rifampicin increased omeprazole metabolism in all subjects irrespective of genotype, which suggested that CYP2C19 enzymatic activity was induced by rifampicin administration for all genotypes. Conversely, while fluvoxamine reduced omeprazole metabolism in subjects carrying the CYP2C19*1 allele, it had no impact on omeprazole pharmacokinetics in subjects without this allele. The genotyping of CYP2C19 may be useful for predicting drug interactions with metabolic inhibitors.

Incremental shuttle walk test as a valuable assessment of exercise performance in patients with pulmonary arterial hypertension.

BACKGROUND: Nearly all clinical trials investigating patients with pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) to evaluate exercise tolerance. The incremental shuttle walk test (SWT), however, has been proposed as a more valid and reproducible alternative to the 6MWT in the evaluation of exercise tolerance in patients with chronic obstructive pulmonary disease. The efficacy of SWT in clinical practice to evaluate the exercise capacity of patients with PAH was investigated. METHODS AND RESULTS: The peak oxygen consumption (pVO2) and oxygen consumption at anaerobic threshold (VO2 at AT), the gold standard for measurement of exercise tolerance, 6MWT and SWT were measured in 19 clinically stable PAH patients (WHO functional class II-III) and the data compared. There was a higher correlation between SWT walk distance and pVO2 than between 6MWT walk distance and pVO2 (r=0.866 and 0.765, respectively; P<0.05), and a higher correlation between SWT walk distance and VO2 at AT than between 6MWT walk distance and VO2 at AT (r=0.775 and 0.587, respectively; P<0.05). No adverse events occurred during the exercise tests. CONCLUSIONS: SWT is a better reflection than 6MWT of exercise tolerance in PAH patients, and thus is a preferable alternative for assessment of exercise tolerance in PAH patients.

Comparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4.

Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 µg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The Cmax and AUC0-8 returned to the control levels on days 3 and 7. In contrast, AUC0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC0-8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h.