Factors affecting serum protein binding of cocaine in humans

Robert Parker, C. L. Williams, Steven Laizure, J. J. Lima

Research output: Contribution to journalArticle

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Abstract

The free (unbound) drug in serum is an important determinant of pharmacologic response. The present study was performed to more completely identify and evaluate factors affecting cocaine binding to human serum proteins. Protein binding was determined by ultrafiltration with [3H] cocaine. Cocaine binding parameters in serum from eight healthy volunteers were determined over a concentration range of 0.003 to 300 μM (0.001100 μg/ml) and indicated cocaine binds to two classes of independent binding sites; one with high affinity [association constant (K(a)) = 0.42 ± 0.09 μM-1] and low capacity (N1 = 12.3 ± 2.9 μM) and one with low affinity and high capacity (γ = 0.41 ± 0.05). Binding was concentration dependent with free fraction increasing from 0.16 ± 0.05 to 0.68 ± 0.02 over this concentration range. The binding capacity was significantly correlated with α-1-acid glycoprotein (AAG) concentration (r2 = 0.71, P = .0009). Binding studies were performed using AAG and human serum albumin (HSA) alone and together in phosphate buffer to determine the specific proteins responsible for cocaine binding. These studies revealed the binding of cocaine to AAG is potentiated by the presence of HSA as K(a) for the first binding site increased from 0,08 μM-1 with AAG alone to 0.46 μM-1 with AAG combined with HSA 4 g/dl. Binding parameter estimates and cocaine free fraction in human serum and AAG 75 mg/dl plus HSA 4 g/dl in phosphate buffer were similar indicating that AAG and HSA are the principal binding proteins in serum. Cocaine binding is pH dependent within the physiological range; as serum pH decreased, free fraction increased and this change in binding is primarily due to a pH-dependent change in the K(a) for the first binding site. The addition of the cocaine metabolites benzoylecgonine, ecgonine methyl ester, norcocaine and cocaethylene had no effect on cocaine binding. These data identify factors that alter cocaine serum protein binding and may partially account for the wide variability in cocaine serum concentrations found in patients experiencing toxicity.

Original languageEnglish (US)
Pages (from-to)605-610
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume275
Issue number2
StatePublished - Dec 1 1995

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Cocaine
Protein Binding
Blood Proteins
Serum Albumin
Serum
Binding Sites
Buffers
Phosphates
Ultrafiltration
Glycoproteins
Healthy Volunteers
Carrier Proteins
Acids

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Factors affecting serum protein binding of cocaine in humans. / Parker, Robert; Williams, C. L.; Laizure, Steven; Lima, J. J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 275, No. 2, 01.12.1995, p. 605-610.

Research output: Contribution to journalArticle

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