Premium
Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood–brain barrier transporters
Author(s) -
Mahar Doan Kelly M.,
Boje Kathleen M. K.
Publication year - 2000
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.242
Subject(s) - pharmacokinetics , pharmacology , blood–brain barrier , endogeny , pharmacodynamics , transporter , chemistry , central nervous system , medicine , biochemistry , gene
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. Copyright © 2000 John Wiley & Sons, Ltd.