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 EC₅₀ (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 EC₅₀, 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/EC₅₀ ratio (dose/EC₅₀) was > 1 (irrespective of endogenous transport inhibition), but highly dependent on K_m1 and V_max1 when dose/EC₅₀ was (a) < 1 (no endogenous transport inhibition) or (b) equal to 1 (with endogenous transport inhibition). Oral input of the endogenous transport inhibition produced a decrease in t_dur when the dose/EC₅₀ 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.