Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study.

AIM: To investigate whether mesna-sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. METHODS: C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine. RESULTS: Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC0-12h decreased (Ptrend < .001), and urine tCys excretion increased (Ptrend = .004). CONCLUSIONS: Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.

Effect on QTc interval by switching from methadone to equipotent R-methadone dose in methadone maintenance treatment patients.

Methadone (R,S-methadone) can prolong the QT interval. R-methadone inhibits cardiac potassium channel function less than S-methadone. We tested if switching from methadone to R-methadone would reduce corrected QT (QTc) intervals in methadone maintenance treatment (MMT) patients. Nine patients, with automatically read QTc intervals ≥450 ms, were required to detect a 20 ms (clinically relevant) reduction in QTc intervals with 15 ms standard deviation (SD) and 90% power. Nine stabilized MMT patients, using median (range) 70 (40-120) mg methadone, were included. Data (ECG recordings, serum samples, and withdrawal symptoms) were collected both before drug intake (Cmin ) and at 3 h after drug intake (Cmax ), and were collected on the day before the switch from methadone to equipotent R-methadone dose and at 14 and 28 days after the switch. A cardiologist calculated QTc intervals retrospectively. Serum electrolytes and methadone concentrations were measured. Mean QTc intervals at Cmin were 472 ms and 422 ms on methadone (automatically and manually read) and 414 ms on R-methadone (manually read). Mean (SD) change in QTc intervals was -8 (10) ms (p = 0.047) at Cmin but non-significant at Cmax . R-methadone showed a concentration-dependent relationship with QTc intervals. Switching to R-methadone reduced QTc intervals, but far less than the 20 ms considered clinically relevant.

Intraindividual Variability in Absolute Bioavailability and Clearance of Midazolam in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Midazolam is the preferred clinical probe drug for assessing CYP3A activity. We have previously shown substantial intraindividual variability in midazolam absolute bioavailability and clearance in patients with obesity before and after weight loss induced by gastric bypass or a strict diet. The objective was to describe intraindividual variability in absolute bioavailability and clearance of midazolam in healthy individuals without obesity. METHODS: This study included 33 healthy volunteers [28 ± 8 years, 21% males, body mass index (BMI) 23 ± 2.5 kg/m2] subjected to four pharmacokinetic investigations over a 2-month period (weeks 0, 2, 4, and 8). Semi-simultaneous oral (0 h) and intravenous (2 h later) midazolam dosing was used to assess absolute bioavailability and clearance of midazolam. RESULTS: At baseline, mean absolute bioavailability and clearance were 46 ± 18% and 31 ± 10 L/h, respectively. The mean coefficient of variation (CV, %) for absolute bioavailability and clearance of midazolam was 26 ± 15% and 20 ± 10%, respectively. Approximately one-third had a CV > 30% for absolute bioavailability, while 13% had a CV > 30% for clearance. CONCLUSIONS: On average, intraindividual variability in absolute bioavailability and clearance of midazolam was low to moderate; however, especially absolute bioavailability showed considerable variability in a relatively large proportion of the individuals.

Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End-Stage Renal Disease.

Drug dosing is challenging in patients with end-stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P-glycoprotein (P-gp)/organic anion-transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (-3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P-gp/OATP activity.