Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study.
Permeability-glycoprotein (P-glycoprotein, P-gp), an efflux transporter at the human blood-brain barrier (BBB), is a significant obstacle to central nervous system (CNS) delivery of P-gp substrate drugs. Using positron emission tomography imaging, we investigated P-gp modulation at the human BBB by an approved P-gp inhibitor, quinidine, or the P-gp inducer, rifampin. Cerebral blood flow (CBF) and BBB P-gp activity were respectively measured by administration of (15)O-water followed by (11)C-verapamil. In a crossover design, healthy volunteers received quinidine and 11-29 days of rifampin treatment during different study periods. CBF and P-gp activity was measured in the absence (control; prior to quinidine treatment) and presence of P-gp modulation. At clinically relevant quinidine plasma concentrations, P-gp inhibition resulted in a 60% increase in (11)C-radioactivity distribution across the human BBB as measured by the brain extraction ratio (ER) of (11)C-radioactivity. Furthermore, the magnitude of BBB P-gp inhibition by quinidine was successfully predicted by a combination of in vitro and macaque data, but not by rat data. Although our findings demonstrated that quinidine did not completely inhibit P-gp at the human BBB, it has the potential to produce clinically significant CNS drug interactions with P-gp substrate drugs that exhibit a narrow therapeutic window and are significantly excluded from the brain by P-gp. Rifampin treatment induced systemic CYP3A metabolism of (11)C-verapamil; however, it reduced the ER by 6%. Therefore, we conclude that rifampin, at its usual clinical dose, cannot be used to induce P-gp at the human BBB to a clinically meaningful extent and is unlikely to cause inadvertent BBB-inductive drug interactions.
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Li
L
Liu
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Ann C
AC
Collier
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Jeanne M
JM
Link
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Karen B
KB
Domino
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
David A
DA
Mankoff
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Janet F
JF
Eary
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Charles F
CF
Spiekerman
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Peng
P
Hsiao
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington.
Anand K
AK
Deo
Department of Pharmaceutics (L.L., P.H., A.K.D., J.D.U.), Department of Medicine (A.C.C.), Division of Nuclear Medicine (J.M.L., D.A.M., J.F.E.), Department of Anesthesiology and Pain Medicine (K.B.D.), and Department of Oral Health Sciences (C.F.S.), University of Washington, Seattle, Washington jash@u.washington.edu.
Jashvant D
JD
Unadkat
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000328:Adult; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008251:Macaca; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D011802:Quinidine / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D012293:Rifampin / Q000097:blood* / Q000494:pharmacology; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011802:Quinidine; D012293:Rifampin