Chronic, Twice-Daily Dosing of an NK2 Receptor Agonist [Lys5,MeLeu9,Nle10]-NKA(4-10), Produces Consistent Drug-Induced Micturition and Defecation in Chronic Spinal Rats.

Acute administration of [Lys5,Me,Leu9,Nle10]-NKA(4-10) (LMN-NKA) produces contractions of the detrusor and rectum with voiding in intact and acutely spinal cord injured (SCI) rats. In the current study, the ability of LMN-NKA (10 µg/kg or 100 µg/kg, subcutaneous [SC], twice a day [bid]) or vehicle to induce voiding and defecation in chronic SCI rats was examined across 30 days. After the last day of administration, voiding response rates and bladder pressure (BP) responses to LMN-NKA (intravenous [IV] and SC) were evaluated under anesthesia. In conscious rats, LMN-NKA (100 µg/kg) produced dose-dependent micturition within 5 min, with response rates >90%, and voiding efficiency >80% in males and >60% in females, which remained stable across the 1-month test period. Similarly, LMN-NKA administration rapidly induced defecation, which also remained stable. Under anesthesia, LMN-NKA increased BP, voiding efficiency, and voiding response rates, which reached 100% at 3 and 10 µg/kg IV in males and females, respectively. SC administration produced 100% response rates in males (30 µg/kg) but only 71% in females (100 µg/kg). Efficacy in rats chronically treated with LMN-NKA was similar to naïve and vehicle-treated rats, except for reduced voiding efficiency in chronically dosed female rats (100 µg/kg). No differences in bladder weights or collagen-to-smooth muscle ratios in histological sections were seen between the groups. Thus neither tolerance, nor sensitization, to LMN-NKA-induced micturition and defecation occurs with chronic administration in rats with chronic SCI. Efficacy was higher in male than in female rats.

Characterization of metabolites and disposition of tertiary amyl methyl ether in male F344 rats following inhalation exposure.

Tertiary amyl methyl ether (TAME) is a fuel additive used to reduce carbon monoxide in automobile emissions. Because of the potential for human exposure, this study was conducted to develop methods for the characterization and quantitation of metabolites in expired air and excreta of rats exposed to a mixture of [13C]- and [14C]TAME ([2,3,4-13C]- and [2-14C]2-methoxy-2-methylbutane). The distribution of TAME in rats was determined following inhalation exposure, and TAME-derived metabolites were characterized in expired air and urine. Male rats were exposed for 6 h via nose-only inhalation to 2500 ppm [14C/13C]TAME, and expired air, urine and feces were collected for up to 7 days. Over 95% of the total recovered radioactivity was excreted by 48 h after exposure. Recovered radioactivity was expired as organic volatiles (44%) and 14CO2 (3%) and excreted in urine (51%) and feces (1%). Both TAME and its metabolite tertiary amyl alcohol (TAA) accounted for > or =90% of the radiolabel in expired air 0-8 h following exposure termination. Three major urinary metabolites of TAME were identified: (1) a direct glucuronide conjugate of TAA; (2) a product of oxidation at the methylene carbon of TAA (2,3-dihydroxy-2-methylbutane); (3) a glucuronide conjugate of metabolite 2. Metabolite 1 accounted for most of the TAME-derived metabolites excreted 0-8 h following exposure termination. Further metabolic products of TAA (metabolites 2 and 3) accounted for most of the excreted TAME-derived metabolites at later time points.

Blood pharmacokinetics of tertiary amyl methyl ether in male and female F344 rats and CD-1 mice after nose-only inhalation exposure.

Interest in understanding the biological behavior of aliphatic ethers has increased owing to their use as gasoline additives. The purpose of this study was to investigate the blood pharmacokinetics of the oxygenate tertiary amyl methyl ether (TAME), its major metabolite tertiary amyl alcohol (TAA) and acetone in rats and mice following inhalation exposure to TAME. Species differences in the area under the curve (AUC) for TAME were significant at each exposure concentration. For rats, the blood TAME AUC increased in proportion with an increase in exposure concentration. For mice, an increase in exposure concentration (100-500 ppm) resulted in a disproportional increase in the TAME AUC. Mice had greater (two- to threefold) blood concentrations of TAA compared with rats following exposure to 2500 or 500 ppm TAME. Mice had a disproportional increase in the TAA AUC with an increase in exposure concentration (100-500 ppm). This difference could result from saturation of a process (e.g. oxidation, glucuronide conjugation) that is involved in the further metabolism of TAA. For each species, gender and exposure concentration, acetone increased during exposure and returned to control values by 16 h following exposure. The source of acetone could be both as a metabolite of TAA or an effect on endogenous metabolism produced by exposure to TAME.