title: Lack of effect of treatment with human recombinant-tumour necrosis factor (HrTNF) on the binding of quinidine to alpha 1-acid glycoprotein (AGP).
abstract: Tumour necrosis factor (TNF) is known to be a key mediator in the acute phase response and its administration has been shown to cause a five fold increase in serum alpha 1-acid glycoprotein (AGP) concentration in the rat. Since, in man, plasma AGP level determines the protein binding of many important drugs (e.g. narcotic analgesics, phenothiazines, antiarrhythmics, calcium channel blockers) likely to be given to patients who will be treated with TNF, it is important to determine if TNF treatment of humans causes a similar increase in AGP concentration and drug binding. Therefore, the plasma protein binding of quinidine and the serum level of AGP were studied over a 4 day period in each of five cancer patients who were treated with human recombinant-tumour necrosis factor (HrTNF) using a dosage schedule of 6-8 x 10(+5) units/m2 daily for 5 days. It was observed that the quinidine binding ratio (the quotient of bound and free concentration in plasma) was highly correlated with the plasma concentration of AGP (r = 0.818) and that the mean pretreatment AGP concentration in the patients was about three times that found in normal subjects. However, no effects of the TNF treatment regime used in the present study could be demonstrated on either plasma AGP concentration or quinidine free fraction. These observations allow the tentative conclusion that HrTNF does not cause a significant increase in serum AGP level in cancer patients whose baseline AGP concentration is high. However, further study of the relationship between TNF treatment and serum AGP level is needed.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
authors.forename: J A
authors.initials: JA
authors.lastname: Barnett
authors.forename: D E
authors.initials: DE
authors.lastname: Brenner
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: D
authors.initials: D
authors.lastname: Lalka
mesh_terms: D000328:Adult; D000368:Aged; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000628:therapy; D009961:Orosomucoid / Q000378:metabolism*; D011485:Protein Binding; D011802:Quinidine / Q000378:metabolism*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: D009961:Orosomucoid; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011802:Quinidine