Increased erythrocyte and protein binding of codeine in patients with sickle cell disease

S. S. Mohammed, Mary M Christopher, P. Mehta, A. Kedar, S. Gross, H. Derendorf

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Erythrocyte binding and plasma protein binding of codeine in sickle cell patients and healthy controls were determined. A reversed-phase HPLC procedure was used for codeine analysis. Codeine was extracted from alkalinized plasma, separated on a CN column, and assayed by fluorescence detection. The erythrocyte-buffer partition coefficient was significantly higher in sickle cell patients (1.72 ± 0.21) than in healthy controls (1.25 ± 0.14). No time dependence of partitioning was observed. The fraction of codeine bound to plasma proteins, determined by ultrafiltration, was significantly higher in sickle cell patients (66.0% ± 8.6%) than in healthy controls (30.5% ± 2.7%). No concentration dependence of erythrocyte or protein binding was observed. Further studies were performed to elucidate the binding mechanisms. From a ghost cell binding study it was concluded that the major binding sites for codeine are in the cell membrane. A decrease in codeine binding was observed in the presence of bilirubin. Codeine binding to α1-acid glycoprotein was found to be minimal. The levels of α1-acid glycoprotein and other glycoproteins in sickle cell patients and healthy controls were measured by glycoprotein electrophoresis. The results showed no significant difference between the two groups. Plasma protein electrophoresis was performed for the two groups. The results showed a significant difference in γ-globulin levels between sickle cell patients and healthy controls. Codeine is known to bind to γ-globulin, a fact that may explain in part the observed increase in the plasma protein binding of codeine in sickle cell patients. Because only the free fraction of the drug can cross biological membranes and is considered to be pharmacologically active, the increase in codeine binding in sickle cell patients may be a reason for the observed decreased response to normal doses of codeine in this population.

Original languageEnglish (US)
Pages (from-to)1112-1117
Number of pages6
JournalJournal of Pharmaceutical Sciences
Volume82
Issue number11
DOIs
StatePublished - 1993
Externally publishedYes

Fingerprint

Codeine
Sickle Cell Anemia
Protein Binding
Erythrocytes
Blood Proteins
Glycoproteins
Globulins
Electrophoresis
Biological membranes
Acids
Ultrafiltration
Cell membranes
Bilirubin
Carrier Proteins
Buffers
Fluorescence
Binding Sites
High Pressure Liquid Chromatography
Cell Membrane

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Increased erythrocyte and protein binding of codeine in patients with sickle cell disease. / Mohammed, S. S.; Christopher, Mary M; Mehta, P.; Kedar, A.; Gross, S.; Derendorf, H.

In: Journal of Pharmaceutical Sciences, Vol. 82, No. 11, 1993, p. 1112-1117.

Research output: Contribution to journalArticle

Mohammed, S. S. ; Christopher, Mary M ; Mehta, P. ; Kedar, A. ; Gross, S. ; Derendorf, H. / Increased erythrocyte and protein binding of codeine in patients with sickle cell disease. In: Journal of Pharmaceutical Sciences. 1993 ; Vol. 82, No. 11. pp. 1112-1117.
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abstract = "Erythrocyte binding and plasma protein binding of codeine in sickle cell patients and healthy controls were determined. A reversed-phase HPLC procedure was used for codeine analysis. Codeine was extracted from alkalinized plasma, separated on a CN column, and assayed by fluorescence detection. The erythrocyte-buffer partition coefficient was significantly higher in sickle cell patients (1.72 ± 0.21) than in healthy controls (1.25 ± 0.14). No time dependence of partitioning was observed. The fraction of codeine bound to plasma proteins, determined by ultrafiltration, was significantly higher in sickle cell patients (66.0{\%} ± 8.6{\%}) than in healthy controls (30.5{\%} ± 2.7{\%}). No concentration dependence of erythrocyte or protein binding was observed. Further studies were performed to elucidate the binding mechanisms. From a ghost cell binding study it was concluded that the major binding sites for codeine are in the cell membrane. A decrease in codeine binding was observed in the presence of bilirubin. Codeine binding to α1-acid glycoprotein was found to be minimal. The levels of α1-acid glycoprotein and other glycoproteins in sickle cell patients and healthy controls were measured by glycoprotein electrophoresis. The results showed no significant difference between the two groups. Plasma protein electrophoresis was performed for the two groups. The results showed a significant difference in γ-globulin levels between sickle cell patients and healthy controls. Codeine is known to bind to γ-globulin, a fact that may explain in part the observed increase in the plasma protein binding of codeine in sickle cell patients. Because only the free fraction of the drug can cross biological membranes and is considered to be pharmacologically active, the increase in codeine binding in sickle cell patients may be a reason for the observed decreased response to normal doses of codeine in this population.",
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