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Titolo:
Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood-brain barrier transporters
Autore:
Doan, KMM; Boje, KMK;
Indirizzi:
SUNY Buffalo, Dept Pharmaceut Sci, Sch Pharm & Pharmaceut Sci, Buffalo, NY14260 USA SUNY Buffalo Buffalo NY USA 14260 & Pharmaceut Sci, Buffalo, NY14260 USA
Titolo Testata:
BIOPHARMACEUTICS & DRUG DISPOSITION
fascicolo: 7, volume: 21, anno: 2000,
pagine: 261 - 278
SICI:
0142-2782(200010)21:7<261:TPAPSO>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMINO-ACIDS; CHOROID-PLEXUS; RAT-BLOOD; L-DOPA; PHENYLALANINE; KINETICS; FLUID; SHEEP;
Keywords:
blood-brain barrier; pharmacodynamics; pharmacokinetics; transport;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Boje, KMK SUNY Buffalo, Dept Pharmaceut Sci, Sch Pharm & Pharmaceut Sci, H517 Cooke Hochstetter, Buffalo, NY 14260 USA SUNY Buffalo H517 Cooke Hochstetter Buffalo NY USA 14260 260 USA
Citazione:
K.M.M. Doan e K.M.K. Boje, "Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood-brain barrier transporters", BIOPHARM DR, 21(7), 2000, pp. 261-278

Abstract

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 modelswere 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 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/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 inhibitor 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. Copyright (C) 2000 John Wiley & Sons, Ltd.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/09/20 alle ore 17:16:18