Influence of N-hexane inhalation on the enantioselective pharmacokinetics and metabolism of verapamil in rats.

Verapamil (VER) is commercialized as a racemic mixture of the (+)-(R)-VER and (-)-(S)-VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP-dependent pathways. N-hexane is a solvent that can alter the metabolism of CYP-dependent drugs. The present study investigated the influence of n-hexane (nose-only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m3) on the kinetic disposition of the (+)-(R)-VER, (-)-(S)-VER, (R)-NOR and (S)-NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC-MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (-)-(S)-VER eutomer (AUC(0-infinity) = 250.8 vs. 120.4 ng/ml/h; P < or = 0.05, Wilcoxon test). The (S)-NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC(0-infinity) ratio of 1.5. The pharmacokinetic parameters AUC(0-infinity), Cl/F, Vd/F, and t(1/2) obtained for VER and NOR enantiomers were not altered by nose-only exposure to n-hexane at concentrations of 88, 176, or 352 mg/m3 (P > 0.05, Kruskal-Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n-hexane at concentrations equal to or higher than the TLV-TWA. This finding is relevant considering that the (-)-(S)-VER eutomer is 10-20 times more potent than R-(+)-VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans.

Occupational exposure to paint solvents and particulate material in car repair shops

Aims: We evaluated solvents and total particulates exposures in auto body repair shops together wiyth a search of painter's related complaints. Methods: 26 painters exposure were evaluated by pumped personal sampling; solvents were retained in charcoal sorbent tubes and the particulates in PVC filters. Painter's personal habits and their work characteristics were obtained through a questionaire, applied in a private interview. For the symptoms the Qq6 questionnaire was used, added of questions about compalints during the painting. Results: High exposures were deteced during spray painting. For solvents, the TLV-STEL adjusted for the mixtures was sursurpassed in six evaluations. However, as repaint is a short-trm operation, it makes the average concentrations weighed for the work shift lower than the TLV-TWA adjusted for the mixtures. Total particulate concentrations had suparssed the TLV-TWA in foru of the evaluations. Symptoms frequency in the Q16 questionnaire was higher for patients than for the controls (Mann-Whitney test U=193; p+0.008), and they showed positive correlations with the age (Spearm r=0.354, t=1.85, p=0.076), the number of years in the profession (Spearman r=0.433, t=2.35, p=0.027) and the alcoholic beverage consumption (Spearman r=0.457, t=2.516, p=0.019). Conclusions: The painting work done at car repair shops can result in high solvent and particulate exposures, although they are short-term operations. Their acute and chronic effects for the painters do not have been clearly evidenced in the present study, continuing deserving multidiciplinary attention...