In vitro and in silico hormonal activity studies of di-(2-ethylhexyl)terephthalate, a di-(2-ethylhexyl)phthalate substitute used in medical devices, and its metabolites.

Plasticizers added to polyvinylchloride used in medical devices can be released into patients' biological fluids. The substitution of di-(2-ethylhexyl)phthalate (DEHP) by alternative plasticizers is essential but their safety must be demonstrated. DEHP, di-(2-ethylhexyl)terephthalate (DEHT) and their metabolites were investigated using level 2 Organization for Economic Co-operation and Development bioassays to screen for in vitro hormonal changes. Differences between the DEHP and DEHT metabolites were observed. Albeit weak, the hormonal activities of DEHT-derived metabolites, e.g., 5-OH metabolite of mono-(ethylhexyl)terephthalate (5-OH-MEHT), were detected and the results of docking experiments performed on estrogen receptor alpha and androgen receptor agreed with the biological results. A co-stimulation of human estrogen receptor alpha and human androgen receptor was also observed. With regard to steroidogenesis, a 16-fold increase in estrogen synthesis was measured with 5-OH-MEHT. Therefore, even if DEHT remains an interesting alternative to DEHP because of its low migration from medical devices, it seems important to verify that multi-exposed patients in neonatal intensive care units do not have urinary levels of oxidized metabolites, in particular 5-OH-MEHT, suggesting a potential endocrine-disrupting effect.

Pharmacokinetics and dialysability of naltrexone in patients undergoing hemodialysis.

The disposition of naltrexone (NLT) (REVIA), an opioid antagonist intended for patients with impaired renal function and with severe intractable itching refractory to regular antipruritic therapy, was characterized. Hemodialysis effects on both efficacy and elimination of NLT also were assessed. We developed a simple, sensitive and selective reverse-phase high-performance liquid chromatographic (HPLC) method for measuring NLT plasma concentration in hemodialysis patients treated to relieve pruritus. NLT and the internal standard, naloxone (NLX) were extracted from plasma using a solid-phase extraction method with sep-pack C18 cartridge. The method was employed to determine both naltrexone pharmacokinetics and dialysability parameters during 4-h in dialyzed patients with chronic renal impairment. Thus, seven patients (2 men, 5 women) with end-stage renal disease and pruritus on regular hemodialysis were included. They received one tablet of NLT (Revia, 50 mg) orally prior dialysis session. The Cmax at the inlet and at the outlet the dialyzer were higher (255+/-117 ng/mL and 206+/-137 ng/ml respectively) in comparison with healthy subjects (9 - 44 ng/mL). The decrease hepatic first-pass metabolism of NLT consecutive to end-stage renal disease and the renal impairment could explain the increased levels of the drug in plasma. Tmax before and after dialysis plates remain unchanged as healthy subjects (approximately 1h). With regard to dialysability, a high dialyzer extraction ratio averating 30 % was found with a low dialysis clearance of 58.70+/-17 mL/min. The amount removed by dialysis is only 1.27 mg. We concluded that hemodialysis has little effect on NLT blood levels, and consequently on drug pharmacokinetics, when the drug is delivered to dialyzed patients following oral route. Thus, dosage adjustement is not required in the presence of advanced dialysis-dependant renal failure. In patients with end-stage renal disease, hemodialysis does not result in clinically significant alterations in the disposition of NLT. Post-dialysis supplementation is not required. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but in view of NLT plasma concentration levels in the patients, a clinician could determine whether dosage adjustment are necessary and, if so, make the required calculations accurately.