title: Biochemical and pharmacokinetic characterisation of two PEGylated variants of dipetarudin.
abstract: Dipetarudin was coupled to polyethylene glycol (PEG)-5000 residues in order to improve its pharmacokinetic profile and to enhance its anticoagulant efficacy. The resulting compounds, mono- and di-PEGylated dipetarudin were purified by gel filtration. Mono-PEGylated dipetarudin exhibited similar activity like its non-conjugated equivalent both in vitro and in vivo. However, di-PEGylated dipetarudin showed longer distribution and elimination half-lives and higher area under the time-concentration curve in comparison with the unmodified inhibitor which may be attributed to decreased renal clearance. Futhermore, ratio k(12)/k(21) decreased when the number of PEG chains coupled to dipetarudin increased. It means that the inter-compartment transfer of dipetarudin, characterised by a fast distribution and a high retention in the peripheral compartment, is reverted by coupling to PEG. Thus, the transfer of mono-PEGylated dipetarudin between these compartments is similar in both senses and the transfer of di-PEGylated dipetarudin is slower from vascular to extravascular compartment than vice versa. Our results show that di-PEGylated dipetarudin produces a better and longer anticoagulant effect than unmodified dipetarudin which is a desirable attribute for future therapeutic application.
authors.affiliation: Instituto Venezolano de Investigaciones Científicas, Laboratorio de Hemostasia y Genética Vascular, Centro de Biofísica y Bioquímica, Caracas 1020A, Venezuela. melopez73@hotmail.com
authors.forename: Mercedes
authors.initials: M
authors.lastname: López
authors.forename: Anne
authors.initials: A
authors.lastname: Koehler
authors.forename: Goetz
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D019540:Area Under Curve; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008956:Models, Chemical; D010843:Pichia / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000493:pharmacokinetics*; D013917:Thrombin / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D011993:Recombinant Fusion Proteins; C493509:dipetarudin; D011092:Polyethylene Glycols; D013917:Thrombin