Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system.
Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
Hoffmann
Gerhard
G
Non-Clinical Safety, F. Hoffmann-La Roche Ltd., Bldg. 70/127, CH-4070 Basel, Switzerland. gerhard.hoffmann@roche.com
Funk
Christoph
C
Fowler
Stephen
S
Otteneder
Michael B
MB
Breidenbach
Alexander
A
Rayner
Craig R
CR
Chu
Tom
T
Prinssen
Eric P
EP
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism*; D043182:Carboxylesterase / Q000502:physiology; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D009713:Nucleotidyltransferases / Q000502:physiology; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000098556:mRNA Guanylyltransferases
D000998:Antiviral Agents; D053139:Oseltamivir; D009713:Nucleotidyltransferases; D000098556:mRNA Guanylyltransferases; C517204:CES2 protein, human; D043182:Carboxylesterase; C535162:oseltamivir carboxylate