Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood--brain barrier transporters.
Pharmacokinetic/pharmacodynamic simulations were performed to assess the feasibility of central nervous system (CNS) drug delivery via endogenous transporters resident at the blood-brain barrier (BBB). Pharmacokinetic models were derived for intravenous bolus dosing of a hypothetical drug in the absence or presence of an endogenous, competing transport inhibitor. These models were linked to CNS pharmacodynamic models where the effect sites were either cell surface receptors or intracellularly localized enzymes. The response of the dependent parameter, the duration of effect (t(dur)), was examined in relationship to changes in the independent parameters, i.e. dose, elimination rate constant (k(e1)), BBB transport parameters (K(m1) and V(max1)) and EC(50) (effective concentration that elicits a 50% response). As expected, t(dur) increased with (a) increases in drug doses, (b) decreases in k(e1) or (c) decreases in EC(50), irrespective of the effect site. Surprisingly, endogenous transport inhibition produced decreases in drug terminal half-life and corresponding decreases in t(dur). Interestingly, t(dur) was independent of assigned transporter K(m) and V(max) when the dose/EC(50) ratio (dose/EC(50)) was >1 (irrespective of endogenous transport inhibition), but highly dependent on K(m1) and V(max1) when dose/EC(50) was (a) <1 (no endogenous transport inhibition) or (b) equal to 1 (with endogenous transport inhibition). Oral input of the endogenous transport inhibitor produced a decrease in t(dur) when the dose/EC(50) range was 0.1-10. These simulations highlight that (a) systemic pharmacokinetic and BBB transport parameters influence t(dur), (b) drug terminal half-life is inversely related to circulating levels of endogenous inhibitors, and (c) oral ingestion of endogenous transport inhibitor(s) reduces t(dur). Overall, these simulations provide insight for the feasibility of rational CNS drug design/delivery via endogenous transporters.
Mahar Doan
K M
KM
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA.
Boje
K M
KM
D000284:Administration, Oral; D019540:Area Under Curve; D001692:Biological Transport / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008962:Models, Theoretical; D010599:Pharmacokinetics
D002352:Carrier Proteins; D004791:Enzyme Inhibitors