Blood-Brain Disposition and Antinociceptive Effects of [D-Penicillamine]enkephalin in the Mouse
نویسندگان
چکیده
Although intravenous administration of [D-penicillamine]enkephalin (DPDPE) produces significant antinociception in rodents, the duration of antinociception is short (;15 min). The present study was conducted to test the hypothesis that duration of antinociception for DPDPE is determined by both systemic and regional disposition (i.e., blood-brain translocation), and that the magnitude of antinociception is related more closely to concentrations in brain tissue than in blood. Systemic disposition was examined after i.v. administration of DPDPE (10–100 mg/kg) to male CD-1 mice. The relationship between antinociception and concentration in blood and brain tissue was assessed by determining antinociception 10 min after administration of DPDPE (10–100 mg/kg); effect versus brain tissue concentration data were fit with pharmacodynamic models to recover EC50 estimates. In addition, the time course of antinociception, as well as blood and brain tissue concentrations, were examined after an i.v. bolus dose (40 mg/kg) of DPDPE. The systemic disposition of DPDPE was nonlinear; both clearance and volume of distribution were dose-dependent. Antinociception increased proportionately with increasing concentrations of DPDPE in blood or brain tissue, with an EC50 of 1.42 6 0.06 mg/g expressed as brain tissue concentration. However, the brain-to-blood concentration ratio also increased with increasing dose, suggestive of saturable translocation of DPDPE across the blood-brain barrier. Antinociception appeared rapidly (within 5 min) and dissipated within ;15 min after a 40 mg/kg i.v. dose. These results suggest that rapid elimination from blood and active efflux from brain limit the duration of action of DPDPE. [D-penicillamine]enkephalin is a cyclic opioid pentapeptide developed as a potential drug candidate for treatment of pain (Williams et al., 1996). DPDPE has been used extensively in receptor binding studies because of its high selectivity for the delta opioid receptor (Mosberg et al., 1983; Toth et al., 1990). DPDPE is resistant to neutral endopeptidase and aminopeptidase, enzymes that are responsible for the rapid degradation of most endogenous enkephalins (Weber et al., 1991), and it is stable during in vitro incubation in various biologic matrices (Chen and Pollack, 1997). In vivo disposition studies in rats also indicated that biotransformation of DPDPE was minimal (Chen and Pollack, 1997). DPDPE elicits antinociception after intrathecal, intracerebroventricular or i.v. administration in rats and mice (Porreca et al., 1987; Weber et al., 1991). Although the duration of action is short, substantial antinociception, with rapid onset, after i.v. administration indicates that DPDPE penetrates the BBB. DPDPE has an apparent permeability coefficient of 5 3 10 cm/min in BMEC, similar to that of antipyrine and propanolol (5–8 3 10 cm/min; Shah et al., 1989). Despite this favorable partitioning, only ;0.06% of the total radioactivity was recovered in whole brain after i.v. administration of H-DPDPE in mice (Weber et al., 1991). Studies in BMEC, with a series of [Met]enkephalin peptides including DPDPE and several DPDPE analogs, revealed a strong relationship between lipophilicity and permeability in BMEC, which suggests that transmembrane diffusion of DPDPE into the brain may occur (Weber et al., 1993). The rapid appearance of a pharmacologic response mediated in the central nervous system with low steady-state brain/blood partitioning suggests an active efflux from the brain as opposed to a limited uptake into the brain. Despite its favorable stability, which has been attributed to conformational restriction due to a cyclic structure (Weber et al., 1992), the residence time of DPDPE in vivo was unexpectedly short, with an elimination half-life of ;14 min (Chen and Pollack, 1996). Examination of the hepatobiliary disposition of DPDPE in rats demonstrated that extensive biliary excretion might be the underlying reason for the short sojourn of the peptide in vivo (Chen and Pollack, 1997). This rapid removal of DPDPE from blood likely is one reason for the short duration of antinociceptive action. To elucidate completely the underlying mechanism(s) responsible for the brief duration of pharmacologic effect, it is Received for publication June 9, 1997. ABBREVIATIONS: DPDPE, [D-penicillamine]enkephalin; BBB, blood-brain barrier; BMEC, bovine brain microvessel endothelial cells; AIC, Akaiki’s Information Criteria; HPLC, high-performance liquid chromatography; PTS, peptide transport system; ANOVA, analysis of variance. 0022-3565/97/2833-1151$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 283, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 283:1151–1159, 1997 1151 at A PE T Jornals on July 8, 2017 jpet.asjournals.org D ow nladed from essential to characterize disposition of the peptide in the systemic circulation and brain tissue (the presumed site of action), and to assess the contribution of these pharmacokinetic properties to pharmacologic action. One study has examined the time course of antinociception in relation to blood and brain tissue concentrations after i.v. administration of H-DPDPE (10 mg/kg) to mice (Weber et al., 1992). However, because the study focused on the effect of peptide structure on disposition and analgesia, the small number of time points at which DPDPE concentrations were determined limited the ability to assess the pharmacokinetic parameters governing DPDPE disposition. No effort has been exerted to examine the relationship between DPDPE disposition and pharmacologic effect. Accordingly, the present study was undertaken to examine the pharmacokinetics of DPDPE in blood and brain tissue of mice, and to correlate antinociceptive action with the disposition of the peptide to gain insight into the factors that determine pharmacologic activity of opioid peptides.
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