Coupling the in vivo performance to the in vitro characterization of PLGA microparticles

The δ-opioid receptor (δOR) holds great potential as a therapeutic target. Yet, clinical drug development, which has focused on δOR agonists that mimic the potent and selective tool compound SNC80 have largely failed. It has increasingly become apparent that the SNC80 scaffold carries with it potent and efficacious β-arrestin recruitment. Here, we screened a relatively small (5120 molecules) physical drug library to identify δOR agonists that underrecruit β-arrestin, as it has been suggested that compounds that efficaciously recruit β-arrestin are proconvulsant. The screen identified a hit compound and further characterization using cellular binding and signaling assays revealed that this molecule (R995045, compound 1) exhibited ten-fold selectivity over µ- and κ-opioid receptors. Compound 1 represents a novel chemotype at the δOR. A subsequent characterization of fourteen analogs of compound 1, however did not identify a more potent δOR agonist. Computational modeling and in vitro characterization of compound 1 in the presence of the endogenous agonist leu-enkephalin suggest compound 1 may also bind allosterically and negatively modulate the potency of Leu-enkephalin to inhibit cAMP, acting as a ‘NAM-agonist’ in this assay. The potential physiological utility of such a class of compounds will need to be assessed in future in vivo assays.

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In vivo and in vitro characterization of rifampicine suppositories

Journal of Drug Delivery Science and Technology ◽

10.1016/s1773-2247(09)50039-1 ◽

2009 ◽

Vol 19 (3) ◽

pp. 217-221

Author(s):

H.M. El-Nahas ◽

F.S. Ghazy ◽

H.A. El-Ghamry ◽

A.M. El-Wsaby

Keyword(s):

In Vitro Characterization

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In vivo and in vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.93.4.1601 ◽

1996 ◽

Vol 93 (4) ◽

pp. 1601-1606 ◽

Cited By ~ 75

Author(s):

K. L. Borden ◽

J. M. Lally ◽

S. R. Martin ◽

N. J. O'Reilly ◽

E. Solomon ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Zinc Binding ◽

Binding Domains ◽

In Vitro Characterization

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In vivo and in vitro trimethadione oxidation activity of the liver from various animal species including mouse, hamster, rat, rabbit, dog, monkey and human

Human & Experimental Toxicology ◽

10.1177/096032719901800102 ◽

1999 ◽

Vol 18 (1) ◽

pp. 12-16 ◽

Cited By ~ 2

Author(s):

E Tanaka ◽

A Ishikawa ◽

T Horie

Keyword(s):

Animal Species ◽

In Vitro Study ◽

Metabolic Clearance ◽

Oxidation Activity ◽

In Vitro Characterization ◽

Demethylase Activity ◽

Total Body

Trimethadione (TMO) has the properties required of a probe drug for the evaluation of hepatic drug-oxidizing capacity and, in this study, we have summarized the in vivo and in vitro metabolism of TMO in various animal species including mouse, hamster, rat, rabbit, dog, monkey and human. In the in vivo study, the plasma TMO level was measured after intravenous or oral (human) administration of TMO at a dose of 4 mg/kg to various animal species. The rate of TMO metabolic clearance in these animal species in vivo was in the order mouse > hamster >rat>rabbit>dog>monkey>human. In the in vitro study, species differences were observed in the cytochrome P450 (P450) content and drug-oxidizing enzyme activity. The content of P450 was monkey> mouse>dog>rabbit>hamster>rat>human. On the other hand, TMO N-demethylation was in the order mouse >hamster >rat >rabbit>dog>monkey>human. There was a good correlation between the mean total body clearance of TMO ( in vivo)andthemeanTMON-demethylase activity ( in vitro) (y=1.7×+0.11, r=0.965, P<0.001). These results show that TMO is a probe agent with metabolic and pharmacokinetic characteristics making it attractive for the in vivo and in vitro characterization of metabolic activity in various animal species.

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