Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously.
METHODS
Experimental laboratory investigations in paraplegic rats.


OBJECTIVE
In order to understand why acute spinal cord injury (SCI) changes the disposition of some, but not all drugs given intravenously (i.v.), pharmacokinetic parameters of drugs with different pharmacological properties were evaluated to determine the influence of SCI on physiological processes such as distribution, metabolism and excretion.


METHODS
Mexico City, Mexico.


METHODS
Rats were subjected to severe SCI (contusion) at T-9 level; pharmacokinetic studies of phenacetin, naproxen or gentamicin were performed 24 h after. These drugs were not chosen as markers because of their therapeutic properties, but because of their pharmacokinetic characteristics. Additional studies including plasma proteins, liver and renal function tests, and micro-vascular hepatic blood flow, were also performed at the same time after injury.


RESULTS
Acute SCI significantly reduced distribution of drugs with intermediate and low binding to plasma proteins (phenacetin 30% and gentamicin 10%, respectively), but distribution did not change when naproxen - a drug highly bound to plasma proteins (99%) - was used, in absence of changes in plasma proteins. Metabolism was significantly altered only for a drug with liver blood flow - limited clearance (phenacetin) and not for a drug with liver capacity-limited clearance (naproxen). The liver function test did not change, whereas the hepatic micro-vascular blood flow significantly decreased after SCI. Renal excretion, evaluated by gentamicin clearance, was significantly reduced as a consequence of SCI, without significant changes in serum creatinine.


CONCLUSIONS
Changes in drug disposition associated to acute SCI are complex and generalization is not possible. They are highly dependent on each drug properties as well as on the altered physiological processes. Results motivate the quest for strategies to improve disposition of selective i.v. drugs during spinal shock, in an effort to avoid therapeutic failure.
García-López
P
P
Laboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, México, DF, México.
Martínez-Cruz
A
A
Guízar-Sahagún
G
G
Castañeda-Hernández
G
G
D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005839:Gentamicins / Q000097:blood* / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D009288:Naproxen / Q000097:blood* / Q000493:pharmacokinetics*; D010615:Phenacetin / Q000097:blood* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000097:blood* / Q000188:drug therapy; D013904:Thoracic Vertebrae / Q000293:injuries
D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005839:Gentamicins; D009288:Naproxen; D010615:Phenacetin