PharmacologyTier 1Medical Sciences concept

Blood-brain barrier drug penetration determinants (P-glycoprotein efflux)

Core concept

CNS penetration determined by lipophilicity, molecular size, protein binding, and active transport -- not simply "is the BBB intact"
Lipophilic, small, unbound (low protein binding) drugs cross more readily by passive diffusion
P-glycoprotein (P-gp) is an efflux pump on the luminal endothelial membrane that actively pumps drugs back out into blood -- reduces CNS entry independent of lipophilicity

P-gp substrates with limited CNS penetration despite reasonable lipophilicity: loperamide (peripheral opioid effect only, no CNS opioid effect at normal dose), many chemotherapy agents, digoxin
P-gp inhibitors (e.g. verapamil, ketoconazole, clarithromycin) -> increased CNS/systemic penetration of P-gp substrates -> toxicity risk (e.g. loperamide CNS depression at high dose with a P-gp inhibitor)
Inflammation (meningitis) disrupts tight junctions -> transiently increases penetration of normally poorly-penetrant drugs (e.g. benzylpenicillin achieves therapeutic CSF levels only when meninges are inflamed)

Choosing an antibiotic for suspected meningitis relies on this: agents with otherwise poor CNS penetration (e.g. many cephalosporins) achieve adequate levels because of inflammation, but penetration falls again as inflammation resolves -- do not under-treat duration expecting sustained penetration
Trap: assuming a drug's usual CNS penetration profile still applies once meningeal inflammation has settled
Loperamide overdose/co-administration with a P-gp inhibitor can cause opioid CNS toxicity (sedation, QT prolongation, respiratory depression) despite loperamide being "non-CNS-penetrant" at normal use

Same P-gp mechanism underlies multidrug resistance in chemotherapy (tumour cells overexpressing P-gp export cytotoxic drugs)
Neonates/infants have a more permeable BBB -> increased CNS drug/toxin penetration relative to adults (relevant to kernicterus, drug toxicity in this age group)
Contrast with placental barrier transfer, which follows similar lipophilicity/size/binding principles but with additional efflux transporters

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