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Toxicological evaluation of μ‐agonists part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo‐alpha‐acetylmethadol HCl (LAAM)
Author(s) -
Borzelleca Joseph F.,
Egle John L.,
Harris Louis S.,
Johnson David N.,
Terrill James B.,
Belleville Jo Ann Nuite
Publication year - 1994
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2550140609
Subject(s) - kidney , medicine , toxicity , endocrinology
This study evaluated levo‐alpha‐acetylmethadol hydrochloride (LAAM), a long‐acting morphine‐like (μ) agonist approved in 1993 to treat opiate dependence. Sprague‐Dawley rate (20/sex/group) were gavaged with doses of 3.0–33.5 mg kg −1 for 30 days followed by a 14‐day drug‐free recovery period. Treatment‐related effects included dose‐dependent CNS depression, decreased food consumption and body weight gain, reddish urine and abdominal staining. Tolerance developed by day 7. Mortality was dose‐dependent; deaths occurred predominantly during the first week. Increased alanine aminotransferase (SGOT, AST) and lactate dehydrogenase (LDH), observed only in high‐dose males, were associated with findings in liver. Decreases in spleen/brain weight and increases in brain/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for high‐dose groups. Kidneys of mid‐ and high‐dose groups displayed intertubular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high‐dose males and mid‐ and high‐dose females. Following the recovery period, decreased body weights and increased brain/body weight ratios occurred in mid‐dose males and low‐dose females. Weights of liver and kidney and organ/brain weight ratios were decreased in mid‐dose males. Histopathological findings observed in kidneys and livers had abated. In summary, acute and repeated administration of LAAM produced a spectrum of activity consistent with its profile as a long‐acting pure μ‐agonist which stimulates microsomal enzymes in rodents. Renal and hepatic effects seen in initially drug‐naive rats treated with morphine‐type agonists are not observed in tolerant individuals stabilized on μ‐agonists to treat opiate dependence.