Pharmacokinetics of Injectable Meloxicam and Buprenorphine in the Naked Mole-Rat (Heterocephalus glaber).

Unique characteristics of the naked mole-rat (NMR) have made it increasingly popular as a laboratory animal model. These rodents are used to study many fields of research including longevity and aging, cancer, circadian rhythm, pain, and metabolism. Currently, the analgesic dosing regimens used in the NMR mirror those used in other rodent species. However, there is no pharmacokinetic (PK) data supporting the use of injectable analgesics in the NMR. Therefore, we conducted 2 independent PK studies to evaluate 2 commonly used analgesics in the NMR: meloxicam (2 mg/kg SC) and buprenorphine (0.1 mg/kg SC). In each study, blood was collected at 8 time points after subcutaneous injection of meloxicam or buprenorphine (0 [predose], 0.25, 0.5, 1, 2, 4, 8, and 24 h). Three NMRs were used per time point for a total of 24 animals per PK study. Plasma concentrations of meloxicam were highest between 0.5 and 1 h postinjection. Levels remained above the extrapolated dog and cat therapeutic threshold levels (390 to 911 ng/mL) for at least 24 h. Plasma concentrations of buprenorphine were highest between 0.25 and 0.5 h postinjection. Levels remained above the human therapeutic threshold (1 ng/mL) for up to 21 h. No skin reactions were seen in association with injection of either drug. In summary, these data support dosing meloxicam (2 mg/kg SC) once every 24 h and buprenorphine (0.1 mg/kg SC) once every 8 to 12 h in the NMR. Further studies should be performed to evaluate the clinical efficacy of these drugs by correlating plasma concentrations with postoperative pain assessments.

Urinary ACE Phenotyping as a Research and Diagnostic Tool: Identification of Sex-Dependent ACE Immunoreactivity.

BACKGROUND: Angiotensin-converting enzyme (ACE) is highly expressed in renal proximal tubules, but ACE activity/levels in the urine are at least 100-fold lower than in the blood. Decreased proximal tubular ACE has been associated with renal tubular damage in both animal models and clinical studies. Because ACE is shed into urine primarily from proximal tubule epithelial cells, its urinary ACE measurement may be useful as an index of tubular damage. OBJECTIVE AND METHODOLOGY: We applied our novel approach-ACE phenotyping-to characterize urinary ACE in volunteer subjects. ACE phenotyping includes (1) determination of ACE activity using two substrates (ZPHL and HHL); (2) calculation of the ratio of hydrolysis of the two substrates (ZPHL/HHL ratio); (3) quantification of ACE immunoreactive protein levels; and (4) fine mapping of local ACE conformation with mAbs to ACE. PRINCIPAL FINDINGS: In normal volunteers, urinary ACE activity was 140-fold less than in corresponding plasma/serum samples and did not differ between males and females. However, urinary ACE immunoreactivity (normalized binding of 25 mAbs to different epitopes) was strongly sex-dependent for the several mAbs tested, an observation likely explained by differences in tissue ACE glycosylation/sialylation between males and females. Urinary ACE phenotyping also allowed the identification of ACE outliers. In addition, daily variability of urinary ACE has potential utility as a feedback marker for dieting individuals pursuing weight loss. CONCLUSIONS/SIGNIFICANCE: Urinary ACE phenotyping is a promising new approach with potential clinical significance to advance precision medicine screening techniques.

Evaluation of Analgesic Patches in Cynomolgus Macaques (Macaca fascicularis).

Opioids are widely used in veterinary and human medicine to manage pain. However, there is a paucity of information in the literature regarding the pharmacokinetics of opioid transdermal patches (TDP) in NHP. Therefore, to determine whether opioid TDP attain therapeutic concentrations in NHP, the pharmacokinetics of fentanyl (25 µg/h) and buprenorphine (10 and 20 µg/h) TDP were evaluated in naïve, adult, male cynomolgus macaques (n = 4) in a crossover study. Plasma opioid levels were determined by tandem liquid chromatography-mass spectrometry. The AUC0-inf for fentanyl and the low and high dose buprenorphine patches were 115 ± 14, 462 ± 74, and 778 ± 344 ng× h/mL, and the plasma half-lifes were 22 ± 4, 77 ± 27, and 42 ± 11 h, respectively. No adverse effects were noted throughout the study. Minimal therapeutic concentrations for fentanyl (0.2 ng/mL) and buprenorphine (0.1 ng/mL) were achieved in all macaques within 8 h of fentanyl and 24 h of buprenorphine TDP application. Therapeutic levels for the fentanyl and low- and high-dose buprenorphine patches were maintained for 96, 120, and 144 h, respectively. These findings suggest that 25-µg/h fentanyl patches should be replaced every 4 d, and the low- and high-dose buprenorphine patches should be replaced every 5 and 6 d, respectively. The results of this study show that fentanyl and buprenorphine patches achieve minimal therapeutic levels for clinically relevant periods of time and should be considered viable options for pain management in cynomolgus macaques.

Pharmacokinetic and tissue distribution study of [14C]fluasterone in male Beagle dogs following intravenous, oral and subcutaneous dosing routes.

The purpose of this work was to compare the pharmacokinetics (PK) and tissue distribution of [14C]fluasterone following intravenous (iv), subcutaneous (sc) and oral (po) administration in male Beagle dogs. The main goal of the investigation was to discover if non-oral routes would alter parameters observed in this study following the administration of [14C]fluasterone. The oral formulation had a lower bioavailability (47%) compared to the sc formulation (84%). Po and sc administration resulted in a similar t(max); however, the observed C(max) following sc dosing was less than half of that after oral dosing. The sc route had the greatest overall exposure (AUC(0-infinity)). Tissue distribution analysis 2 h post-intravenous dosing showed that connective tissue (adipose and bone), liver, and skeletal muscle accumulated relatively high levels of fluasterone. The majority of the dose was retained during the first 24 h. Elimination of [14C]fluasterone-derived radioactivity following intravenous dosing resulted in urine and feces containing 7.6% and 28%, respectively, of the total dose over the first 24 h. Elimination of [14C]fluasterone-derived radioactivity following subcutaneous dosing resulted in 4.6% in urine and 7.8% in feces of the total dose over the first 24 h. Following oral dosing, elimination resulted in 3.8% in urine and 36% in feces over the first 24h. In conclusion, the sc route of administration offers some advantages to po and iv due to the prolonged release and increased retention through 24 h.

Comparison of pharmacokinetic and pharmacodynamic profiles of aspirin following oral gavage and diet dosing in rats.

Aspirin is one of the oldest drugs and has been purported to have multiple beneficial effects, including prevention of cardiovascular disease and cancer, in addition to its original indication for treatment of inflammation, fever and pain. In cancer chemoprevention studies using animal models, two methods of aspirin administration have been employed: oral gavage and diet. The untested assumption was that exposure and the resultant pharmacological effects are similar for these two administration methods when dosing is normalized on the basis of mg/kg body weight/day. This study examined and compared time-dependent plasma and colon mucosal concentrations of aspirin metabolite salicylate (aspirin concentrations were below level of quantification), plasma thromboxane B(2) concentrations, and colon mucosal prostaglandin E(2) concentration following these two different dosing paradigms in rats. Diet dosing yielded relatively constant plasma and colon salicylate concentration vs. time profiles. On the other hand, oral gavage dosing led to a rapid peak followed by a fast decline in salicylate concentration in both plasma and colon. Nevertheless, the exposure as measured by the area under plasma or colon concentration-time curve of salicylate was linearly related to dose irrespective of the dosing method. Linear relationships were also observed between colon and plasma salicylate areas under the curve and between colon prostaglandin E(2) and plasma thromboxane B(2) areas under the curve. Therefore, more easily accessible plasma salicylate and thromboxane B(2) concentrations were representative of the salicylate exposure and prostaglandin E(2) pharmacodynamic biomarker in the target colon, respectively.