Ceftriaxone pharmacokinetics in the central nervous system

Area of Science:

• Pharmacokinetics
• Neuroscience
• Drug Transport

Background:

• The choroid plexus actively transports many penicillins and cephalosporins from cerebrospinal fluid (CSF) to blood.
• Understanding the transport mechanisms of antibiotics like ceftriaxone is crucial for optimizing their efficacy and safety within the central nervous system (CNS).

Purpose of the Study:

• To investigate the in vitro and in vivo transport and metabolism of ceftriaxone across the choroid plexus.
• To compare the affinity of ceftriaxone for the choroid plexus transport system with that of penicillin G.

Main Methods:

• In vitro studies using isolated choroid plexus from New Zealand White rabbits incubated with radiolabeled [14C]ceftriaxone.
• In vivo studies involving intraventricular injection of [14C]ceftriaxone and [3H]mannitol in New Zealand White rabbits, followed by analysis of CSF clearance.

Main Results:

• In vitro, [14C]ceftriaxone exhibited saturable, probenecid-sensitive accumulation in the choroid plexus, but with significantly lower affinity compared to [14C]penicillin G.
• Ceftriaxone was a much weaker inhibitor of [14C]penicillin G accumulation than penicillin G itself (IC50 = 1.6 mM vs. 0.07 mM).
• In vivo, [14C]ceftriaxone clearance from CSF was comparable to [3H]mannitol, suggesting transport via simple diffusion rather than active transport.

Conclusions:

• Ceftriaxone demonstrates minimal affinity for the choroid plexus active transport system responsible for eliminating penicillins and cephalosporins from the CSF.
• Unlike penicillin G, ceftriaxone's transport from CSF to blood appears to be primarily governed by passive diffusion, influencing its CNS pharmacokinetics.