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 (C max ) and the area under the plasma concentration-time curve from 0 to 8 h (AUC 0-8 ) 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 C max and AUC 0-8 returned to the control levels on days 3 and 7. In contrast, AUC 0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC 0-8 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.Key words organic anion-transporting polypeptide; cytochrome P450; grapefruit juice Food and medication are often taken together. However, certain foods interact with drugs by altering mechanisms that are important determinants of systemic drug availability. In particular, grapefruit juice is known to alter the pharmacokinetics of over 30 prescription drugs by affecting their bioavailability.1-3) The mechanism of this interaction is inhibition of intestinal cytochrome P450 (CYP) 3A4 activity and increased systemic exposure of CYP3A4 substrates. [4][5][6][7][8] In 2012, the United States Food and Drug Administration issued a press release to warn consumers that the intake of grapefruit juice along with medication could cause dangerous side effects. 9)Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of the organic anion-transporting polypeptide (OATP) uptake transporter, which is a family of membrane solute carrier (SLC) transporters. OATP influences the intestinal absorption of several drugs in clinical use. [10][11][12][13][14] Grapefruit juice decreases the plasma concentrations of some drugs including β-adrenoceptor blocking agents and antihistamines by this mechanism. For example, grapefruit juice was reported to reduce the area under the plasma concentration-time curve (AUC) value for fexofenadine to a mean value of 58% of that when the drug was administered with the corresponding volume of water.10) Furthermore, celiprolol, ...

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp chievement of reliable results in clinical trials requires an accurate assessment technique. Many clinical trials investigating pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) as a clinical endpoint. Measurement of peak oxygen consumption (pV O2) and oxygen consumption at anaerobic threshold (V O2 at AT) via indirect calorimetry provides an objective, reliable and non-invasive technique to assess exercise tolerance in patients with various cardiac diseases. Furthermore, V O2 at AT describes the highest V O2 that the patient can sustain without developing lactic acidosis, and appears to be an independent marker of PAH severity. 1 In the Sitaxsentan Therapy for Pulmonary Arterial Hypertension (STRIDE-1) study, pV O2 was adopted as the clinical endpoint. 2 Measurement of pV O2, however, requires sophisticated equipment, laboratory facilities, and highly trained personnel. As a result, this test is not widely used and is often confined to large hospitals or research centers. These tests are also expensive and time-consuming, and may not be practical for frequent assessments or large groups of patients. Because of these limitations, field exercise tests such as the submaximal 6MWT have been developed as inexpensive and simple alternative measures of exercise tolerance. 3 The 6MWT measures the distance a patient can voluntarily traverse in a 6-min period. The test protocol, however, is selfpaced, difficult to standardize, and potentially influenced by motivation and encouragement. In addition, the 6MWT has only a moderate correlation with pV O2, 4 and is not a reliable predictor of mortality in patients with congestive heart failure. 5 The development of a simple objective field test that is more highly predictive of pV O2 and easily standardized and used is therefore desirable for patients with PAH.An incremental, externally paced 10-m shuttle walk test (SWT) has been developed for patients with chronic airway limitation. This test is highly reliable and reproducible after only 1 practice walk. 6 In contrast, the 6MWT requires at least 2 practice trials to obtain reliable results. 3 Most importantly, SWT performance relates strongly to pV O2 (r=0.88) in patients with chronic airway limitation, 7 and a strong relationship 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.

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To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4–5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration–time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.

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Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients take these agents simultaneously in the morning and the evening. The aim of this study was to examine the pharmacokinetics of sildenafil which was interfered with bosentan administration to ascertain whether these agents should be given concomitantly or separately. A two-way crossover study was conducted in 6 PAH patients with combination therapy of sildenafil and bosentan. Participants underwent the sequence of treatment phases: phase S (sildenafil administered 3 h before bosentan); phase B (bosentan administered 3 h before sildenafil); and phase C (administered concomitantly). Blood samples were collected on the last day of each phase. There was no significant difference in maximum plasma concentration or area under the plasma concentration-time curve (AUC 0-8) between phase C and phase S (95.5 ± 24.8 vs. 72.9 ± 40.9 (p = 0.07), 209.7 ± 81.8 vs. 180.2 ± 126.4 (p = 0.24), respectively) or between phases C and B (87.8 ± 42.0 vs. 99.6 ± 33.9 (p = 0.59), 197.2 ± 88.2 vs. 240.7 ± 121.8 (p = 0.19), respectively) (ng/mL, mean ± standard deviation). Large intra-and inter-individual variability in sildenafil concentration was noted. The timing of administration of sildenafil and bosentan does not significantly influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned about the timing of administration of these drugs to maximize the sildenafil concentration.

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