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 oti-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.

Alpha 1‐acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria.

“…Cytokines, notably tumour necrosis factor (TNF), may be relevant to this (Chen et al, 1990) as these mediators are variably increased in malaria (Kwiatkowski et al, 1991) and TNF has been shown to increase AAG synthesis in isolated hepatocytes. TNF does not alter the binding properties of AAG (Barnett et al, 1989). In this study plasma concentrations of AAG in acute malaria were over twice those in healthy adult controls.…”

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“…Charge-specific alterations of drug binding in plasma have been found in several diseases accompanied by APR, using equilibrium dialysis and ultrafiltration techniques [17][18][19][20][21][22]. Leukemia, sepsis, and trauma decreased the plasma protein binding of anionic drugs (etoposide [20], teniposide [21], and phenytoin [22]), but substantially increased the binding of cationic drugs (disopyramide [17], quinidine [18], and methadone [19]).…”

“…In most drug-binding studies, the free fractions of drugs in plasma were measured by equilibrium dialysis or ultrafiltration [17][18][19][20][21][22], time-consuming and labor-intensive methods that are not clinically applicable. The changes in the drugbinding ability of APPs are expected to have an effect on the efficiency of therapeutic intervention and must be evaluated in clinically relevant conditions.…”