Reduced urinary 6beta-hydroxycortisol to cortisol ratios in patients with liver cirrhosis.

While the urinary concentration ratio of 6beta-hydroxycortisol (6beta-HC) to cortisol (C) in 24-h urine samples is an established parameter for the induction of hepatic cytochrome P450 (CYP) 3A activity, it remains unclear whether it would be reduced in association with chronic liver damages. To clarify this issue we measured this parameter in 12 patients with chronic hepatitis, 15 patients with liver cirrhosis and 12 healthy subjects. Urinary 6beta-HC and C were assayed with high-performance liquid chromatography with ultraviolet absorption. Multiple regression analysis was performed to search for which biochemical or demographic parameter(s) would be associated with the overall variability of urinary 6beta-HC/C ratios. Results showed that the mean (+/-S.D.) 6beta-HC/C ratio obtained from the patients with liver cirrhosis (4.3+/-2.6), but not that from patients with chronic hepatitis (7.4+/-7.2), was significantly (P<0.05) lower than that obtained from the healthy controls (11.8+/-8.3). It was also revealed that among the clinical parameters examined (e.g. serum transaminases concentrations) only serum albumin concentrations were correlated significantly (R=0.61, P<0.05) with the urinary 6beta-HC/C ratio. In conclusion, the present study implies that that the reduced urinary 6beta-HC/C ratios in patients with liver cirrhosis may be associated with attenuated hepatic CYP3A activity in these patients.

Differential pharmacokinetics of theophylline in elderly patients.

The clinical use of theophylline as a first-line bronchodilator has declined during the last two decades. However, in many clinical settings, such as an emergency bronchial asthma attack, theophylline may have a first-line role, in combination with beta(2)-adrenoreceptor agonists and corticosteroids, for improving the asthmatic status. Furthermore, many therapeutic mechanisms of theophylline for bronchial asthma have been reported, and recent studies have suggested that theophylline therapy may have a beneficial role in the management of chronic stable asthma as well as exacerbated disease. However, theophylline has a low therapeutic index because the bronchodilation it produces has a linear relationship with logarithmic increases in serum concentration for the therapeutic range of 5-20 mg/L. Thus, the knowledge of its basic pharmacokinetics and the factors that can alter its clearance is clinically relevant for physicians. Especially when used in elderly asthmatic patients, dosage adjustment of theophylline is a requisite since the elderly have several risk factors that may increase the plasma theophylline level, such as reduced clearance, various underlying diseases and multiple coadministered drugs. After theophylline treatment has been initiated, therapeutic drug monitoring is required.

Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol.

OBJECTIVE: A 7-day triple therapy with lansoprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for eradication of Helicobacter pylori. Because clarithromycin is a potent inhibitor of cytochrome P450 (CYP) 3A, we investigated whether the standard triple therapy with clarithromycin would elicit clinically relevant CYP3A inhibition and alter CYP3A-mediated lansoprazole disposition in H pylori-positive patients. METHODS: Twenty H pylori-positive patients with peptic ulcer disease were randomly assigned to 2 groups: One group received 200 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days; the other group received 400 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days. Ten healthy control subjects received 30 mg lansoprazole and 750 mg amoxicillin at 8 am and 8 pm for 7 days but did not receive clarithromycin. Urine samples were collected for 3 hours (from 8 am to 11 am) for urinary 6beta-hydroxycortisol and cortisol assay, and midpoint (at 9:30 am) plasma samples for cortisol assay were obtained from all participants before the drug therapy (day 0) and on day 7. In vivo CYP3A activity was assessed by the partial cortisol clearance by means of the formation of 6beta-hydroxycortisol (CL(cortisol-->6beta-hydroxycortisol)) and the urinary 6beta-hydroxycortisol/cortisol ratio. Additional plasma samples for lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone assay were obtained at 11 am on day 7. RESULTS: The groups of patients given 400 and 800 mg/day clarithromycin for H pylori eradication therapy showed 39% (from 2.20 +/- 1.29 to 1.35 +/- 0.88 mL/min [day 0 versus 7, mean +/- SD]; P <.05) and 68% (2.40 +/- 1.22 to 0.76 +/- 0.51 mL/min; P <.05) reductions in CL(cortisol-->6beta-hydroxycortisol), respectively. In contrast, the control subjects given lansoprazole and amoxicillin without clarithromycin showed no significant changes in CL(cortisol-->6beta-hydroxycortisol). The urinary 6beta-hydroxycortisol/cortisol ratio also decreased significantly (P <.05) in the patient groups but not in the control subjects. The mean 3-hour plasma lansoprazole levels elevated in proportion to the doses of clarithromycin: 385 +/- 338 ng/mL for the control subjects, 696 +/- 797 ng/mL for the H pylori-positive patients given 400 mg/day clarithromycin, and 947 +/- 806 ng/mL for the H pylori-positive patients given 800 mg/day clarithromycin (P <.05 versus the control subjects). No significant differences were observed among the groups in the mean plasma ratios of 5-hydroxylansoprazole or lansoprazole sulfone to lansoprazole. CONCLUSIONS: The 7-day H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole may elicit substantial inhibition of in vivo CYP3A activity. Although resultant elevations in plasma lansoprazole concentrations may be beneficial for H pylori eradication, caution must be exercised for possible drug interaction with a concomitantly administered CYP3A substrate (s) in patients undergoing H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole.