Physicochemical and transport properties of small-molecule drugs and the peptide ProTx-II employed in peripheral nerve and CNS tissue distribution studies

DrugsMolecular MassacLogPaTPSAaPassive PermeabilityPermeability ClassificationbP-gp and/or BCRP Substrateb
Carbamazepine2362.446652cHigh passive permeability, CNS drugcNot a P-gp substratec
Haloperidol3753.841286cHigh passive permeability, CNS drugcNot a P-gp substratec
Ralfinamide3022.564355dHigh passive permeabilitydNot a P-gp substrated
Ranitidine3140.67867.5cLow passive permeabilitycWeak P-gp substratec
Atenolol266−0.118512cModerate passive permeabilitycNot a P-gp substratec
Minoxidil209−2.19126cModerate passive permeabilitycNot a P-gp substratec
Dantrolene3141.6124453eHigh passive permeabilityeBCRP specific substratee
Loperamide4774.744456cHigh passive permeabilitycP-gp substratec
Mesoridazine3864.624149cHigh passive permeability, CNS drugcP-gp substratec
Imatinib4934.486201eHigh passive permeabilityeP-gp and BCRP substrate
Cyclosporine A12021427962.6fModerate passive permeabilityfP-gp substrateg
ProTx-II3826NCNCNMLikely very low for a peptide with high MMNM
  • MM, molecular mass; NC, not calculated; NM, not measured; TPSA, topological polar surface area.

  • a The cLogP was calculated by BioByte version 4.3 (Biobyte, Claremont, CA); TPSA was calculated by the method developed by Ertl et al. (2000).

  • b Passive permeability is arbitrarily classified as follows: <10 nm/s, low passive permeability; 10–100 nm/s, moderate passive permeability; >100 nm/s, high passive permeability; molecular mass >1000 is defined as high molecular mass; ranitidine is defined as a weak P-gp substrate because the efflux ratio in the absence of GF120918 in Madin-Darby canine kidney II (MDCKII)-MDR1 cells is 1.6, whereas other P-gp/BCRP substrates have reported efflux ratios greater than 2.

  • c Passive permeability was measured in MDCKII-MDR1 cells obtained from The Netherlands Cancer Institute in the presence of GF120918 (2 µM) at pH 7.4 (Mahar Doan et al., 2002; Thiel-Demby et al., 2009) or obtained from the National Institutes of Health in the presence of GF120918 (2 µM) at pH 7.4 (Summerfield et al., 2007).

  • d Artificial membrane permeability was reported herein (unpublished data). That the compound was not being recognized by P-gp was inferred from the Kp,uu,br value in rats.

  • e Passive permeability was measured in MDCKII-BCRP cells in the presence of 0.2 µM of Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester] and 1 µM of LY335979 [(R)-4-[(1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c)cycloheptan-6-yl]-α-[(5-quinoloyloxy)methyl]-1-piperazine ethanol trihydrochloride] at pH 7.4 (Liu et al., 2017).

  • f Passive permeability was measured in Caco-2 cells obtained from the American Type Culture Collection (Manassas, VA) in the presence of 1 μM GF120198 (von Richter et al., 2009).

  • g Cyclosporine A transported by P-gp was reported by Polli et al. (2001).