Effect of dimethyl sulfoxide on N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity.
Dimethyl sulfoxide (DMSO) is frequently used as a solvent to assist in dissolving compounds which are not readily soluble in other injection vehicles. The purpose of this study was to determine the suitability of DMSO as a vehicle for administering the nephrotoxicant, N-(3,5-dichlorophenyl)succinimide, (NDPS) and two nephrotoxicant NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA). Male Fischer 344 rats (4/group) were administered a single intraperitoneal injection of NDPS (0.4 or 0.8 mmol/kg), NDHS (0.1 or 0.2 mmol/kg), or NDHSA (0.1 or 0.2 mmol/kg) dissolved in 25% DMSO in sesame oil or 100% sesame oil (2.5 ml/kg), while control rats received vehicle only. Renal function was then monitored at 24 and 48 h. Including DMSO in the vehicle markedly attenuated NDPS 0.4 mmol/kg-induced nephrotoxicity and reduced NDPS 0.8 mmol/kg-induced renal effects. Thus, the magnitude of the attenuating effect of DMSO depended in part on the nephrotoxicant dose of NDPS. In addition, NDHS nephrotoxicity was not altered by DMSO and only slight effects on NDHSA nephrotoxicity were observed. These results suggest that DMSO is capable of attenuating NDPS nephrotoxicity, and that the primary mechanism of this interaction might be due to an inhibition of the biotransformation of NDPS to NDHS.
Rankin
G O
GO
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25704-9388, USA.
Beers
K W
KW
Nicoll
D W
DW
Anestis
D K
DK
Ball
J G
JG
Valentovic
M A
MA
Brown
P I
PI
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001711:Biotransformation; D001806:Blood Urea Nitrogen; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005659:Fungicides, Industrial / Q000378:metabolism / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D012715:Sesame Oil / Q000737:chemistry; D013329:Structure-Activity Relationship; D013386:Succinates / Q000008:administration & dosage / Q000633:toxicity*; D013388:Succinimides / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
D005659:Fungicides, Industrial; D013386:Succinates; D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide; C070595:N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid; D012715:Sesame Oil; D000410:Alanine Transaminase; D004121:Dimethyl Sulfoxide