Phenylacetylglycine, a putative biomarker of phospholipidosis: its origins and relevance to phospholipid accumulation using amiodarone treated rats as a model.
Amiodarone was given to male Sprague-Dawley rats at a dose of 150 mg kg(-1) day(-1) for 7 consecutive days to induce phospholipidosis in the lungs of treated rats. Amiodarone was given alone or concurrently with phenobarbitone. Animals given amiodarone had raised total phospholipid in serum, lung and lymphocytes, and elevated lyso(bis)phosphatidic acid (LBPA) in all tissues. Urinary and plasma phenylacetylglycine (PAG) and hepatic portal:aortal phenylacetate (PA) ratio were increased, whereas hepatic phenylalanine hydroxylase (PAH) activity and plasma phenylalanine:tyrosine ratio were not affected. Phenobarbitone treatment increased hepatic total P450 content and induced 7-pentoxyresorufin O-dealkylatian (PROD) activity, as expected, but had no effect on any other biochemical parameter. Plasma amiodarone concentration was reduced in rats co-administered both drugs and phospholipid accumulation in target tissues was attenuated compared with rats treated with amiodarone alone. However, phenobarbitone co-administration failed to alter the magnitude of response with regards to urinary PAG excretion and plasma concentration of its precursors after amiodarone treatment. Increased intestinal absorption of PAG precursors probably resulted in the raised urinary PAG after amiodarone treatment. Urinary PAG correlated weakly with serum, lymphocyte and lung phospholipids. However, urinary PAG excretion was similar in rats dosed solely with amiodarone or in combination with phenobarbitone, despite the fact that the degree of phospholipid accumulation was far less in rats given the combined treatment. Nevertheless, urinary PAG was raised only in animals exhibiting abnormal phospholipid accumulation in target tissues and may thus be useful as a surrogate biomarker for phospholipidosis.
Delaney
Jane
J
Safety Assessment, GlaxoSmithKline, Ware SG12 0DP, UK.
Neville
William A
WA
Swain
Aubrey
A
Miles
Adam
A
Leonard
Michael S
MS
Waterfield
Catherine J
CJ
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008064:Lipidoses / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D009929:Organ Size; D010634:Phenobarbital / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D015415:Biomarkers; D008055:Lipids; D010743:Phospholipids; C022050:phenylacetylglycine; D000638:Amiodarone; D005998:Glycine; D010634:Phenobarbital