The University of British Columbia

About the Principal Investigator

	E-mail: kwasan@mail.ubc.ca Phone: 604-822-4889

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Training Environment

The Role of Lipids and Lipoproteins in Modifying the Biological Activity of Water-Insoluble Drugs

The plasma lipoprotein distribution of potential drug candidates is not commonly studied. For some hydrophobic drug candidates, attainment of similar plasma free drug levels has not been associated with uniform production of pharmacological activity in different animal species. It is well known that plasma lipoprotein lipid profiles vary considerably between different animal species. In addition, human disease states can significantly influence plasma lipoprotein profiles resulting in altered drug therapeutic outcomes. A plausible explanation for these findings may be a result of lipoprotein drug transport within the systemic circulation. Elucidation of the mechanisms that dictate the lipoprotein binding of drugs may yield valuable insight into the factors governing the pharmacological activity and potential toxicity of these compounds. Furthermore, utilizing these factors to target compounds specifically to one lipoprotein subclass over another could, potentially, improve the drug’s efficacy and safety.

Over the past 14 years, my laboratory has published a number of studies and has established the experimental methodologies necessary to justify the importance of investigating the role of lipids and lipoproteins in modifying the biological activity of water-insoluble drugs. With these research tools in place, my laboratory has now demonstrated and provided the potential mechanisms by which water-insoluble drugs interact with lipids and lipoproteins and how these interactions impact on the absorption, distribution, efficacy, toxicity and metabolism of such compounds.

In the larger perspective, these studies have increased the understanding of the mechanisms involved in serum distribution of hydrophobic drugs. In contrast to albumin protein binding, lipoprotein binding of drugs is often overlooked and so the role of lipoproteins as possible intravascular carriers for hydrophobic compounds and their involvement in modifying the biological effects of drugs is a novel and pharmaceutically important discovery. Recently, the FDA (Spring 2002) has suggested that lipoprotein-drug distribution studies should be considered as part of any new IND application that contains a hydrophobic compound. In addition many pharmaceutical companies screen hydrophobic compounds for plasma lipoprotein distribution.

The Wasan lab is actively engaged in the UBC-Neglected Global Diseases Initiative and recently has published work in this area. As a publicly funded institution, the University of British Columbia believes that universities have a fundamental commitment and moral responsibility to advance the public good. In keeping with this, the Global Access Initiative (www.uilo.ubc.ca/about/initiatives/global.html) has enabled UBC to harness the economic potential of University innovations to ensure their development, while at the same time enhancing their social benefit by ensuring fair and affordable access for developing countries. The opportunity exists to harness Canada’s existing research resources and well-respected reputation in international aid to fulfill a moral commitment to the developing world, to win technical leadership in a field of growing scientific and commercial importance, and to protect the health of all populations.

The Neglected Global Diseases Initiative (NGDI; www.ngdi-ubc.com) will bring together the technical expertise and perspectives of a variety of disciplines at UBC – including bench science, pharmaceutical and health research, business, social policy, and law – to investigate truly innovative and effective ways of breaking down the present barriers to success in producing affordable, life-sustaining medicines for the treatment of the world’s most neglected diseases.

Projects

The Wasan Laboratory is currently conducting research in the following areas:

i. Investigation into whether the lipoprotein binding of drugs (i.e. amphotericin B) modify their pharmacological toxicity and plasma disposition (i.e. pharmacokinetics).

ollectively our research in this area has been cited over 350 times in the past decade. A number of key papers with several compounds (i.e. Amphotericin B, Cyclosporine, Halofantrine, Nystatin, E5564, Clozapine) have been published demonstrating the importance of drug association with plasma lipoproteins.Several key papers are highlighted below

1. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery. Published in Nature Reviews Drug Discovery in January 2008. This paper highlights the historical perspective and summarizes our latest research in the area of lipoprotein-drug interactions.
2. Enhanced Amphotericin B Nephrotoxicity in Intensive Care Patients with Elevated Levels of Low-Density Lipoprotein Cholesterol (Clinical Infectious Diseases 24:78-80; 1997). This is the first published paper to suggest that patients with higher serum LDL cholesterol concentrations are more susceptible to amphotericin B-induced kidney toxicity.
3. Pharmacokinetics, Lipoprotein Distribution and Renal Toxicity of Amphotericin B (AmpB) and Amphotericin B Lipid Complex (ABLC) in Cholesterol-Fed Rabbits (Antimicrob. Agents Chemother. 1998). This is the first in a set of papers published to demonstrate rabbits with a higher total and LDL cholesterol concentrations are more susceptible to amphotericin B-induced renal toxicity following Fungizone but not ABLC administration.
4. Lipid Transfer Protein I Facilitated Transfer of Cyclosporine from Low- to High-Density Lipoproteins is only partially dependent on its Cholesteryl Ester Transfer Activity (JPET 1998; Pharmaceutical Research 1999 & 2002; Biochemical Pharmacology 2002) This research suggests that a novel plasma transfer protein, Lipid Transfer Protein, facilitates the transfer of different drugs (i.e. amphotericin, cyclosporine A) among different lipoprotein subclasses. This is the first set of papers with empirical evidence of the role of LTP in redistribution of drug into the lipoprotein subclasses.

ii. Investigating the cardiovascular effects of a novel class of breast cancer agents called aromatase inhibitors in postmenopausal women.

1. Study which reported that the aromatase inhibitor, Letrozole, does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy (Ann Oncol. 2005; 16(5):707-15.).

iii. Published research investigating the role of lipid profiles in schizophrenia therapy.

1. Study which reported that Risperidone augmentation of clozapine for treatment resistant schizophrenia offered no benefit for severity of symptoms, and may increase the risk for cognitive impairment and glucose dysregulation. (Accepted in The New England Journal of Medicine, November 8th 2005; In Press February 2006).
2. Study which reported that modified in vitro lipid profiles can modify the lipoprotein distribution of clozapine. (Am. J. Psychiatry 158:949-951, June 2001)

Selected Publications

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