Relationship between theophylline concentration in plasma and saliva of man

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/‐ 0.24 (s.d.) and showed no time‐ dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/‐ 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/‐ 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/‐ 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non‐specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.

Section: Discussionsupporting

confidence: 91%

The kinetics of salivary elimination of cyclophosphamide in man.

Juma¹,

Rogers²,

Trounce³

1979

“…The degree of binding observed in this study is similar to that reported by Fleetham et al (1979), for healthy subjects, but much lower than that reported by Mangione et al (1978), Simons et al (1979), Koysooko et al (1974), Lesko et al (1981) and Aslaksen et al (1981). Vallner et al (1978) observed that the binding of theophylline in serum is pH-dependent.…”

Section: Discussionsupporting

confidence: 85%

Binding of theophylline in human serum determined by ultrafiltration and equilibrium dialysis.

Brørs¹,

Sager²,

Sandnes³

et al. 1983

1 Binding of theophylline (80 ,tmol/l) was determined in serum from healthy subjects by equilibrium dialysis and by ultrafiltration, using [3H]-theophylline, at 22°C and at different pH-values. pH was regulated by gassing with CO2 or by dialysing the serum against a phosphate buffer before use. 2 Binding of theophylline in serum was 34-38% determined by equilibrium dialysis and 41-45% determined by ultrafiltration at pH 7.4-7.5. The protein concentration in serum decreased by 12-16% during equilibrium dialysis and increased by 20% during ultrafiltration. The intersubject variation in binding was small. 3 Binding of theophylline in serum was pH-dependent with 25-30% bound at pH 7.0 and 58-60% bound at pH 8.1-8.3. Binding was significantly correlated to the fraction of ionized theophylline. 4 The binding of theophylline in normal human serum is about 35 40% at pH 7.4 and 22°C. The difference in binding observed between equilibrium dialysis and ultrafiltration may be explained by the opposite changes in protein concentration during the experiment. 5 Control of pH is necessary to obtain physiologically relevant data on drug binding in serum.

“…study was much greater than that observed by many other authors (Koysooko et al, 1974;Aranda et al, 1976;Piafsky et al, 1977;Mangione et al, 1978;Simons et al, 1979;Lesko et al, 1981). We believe that this may relate to methodological differences.…”

Section: Normal Subjectscontrasting

confidence: 49%

Determinants of the plasma protein binding of theophylline in health.

Buss¹,

Leopold²,

Smith³

et al. 1983

1 The plasma protein binding of theophylline was determined after addition of ['4C]-theophylline (15 ,g/ml) to plasma from 24 healthy drug-free volunteers and equilibrium dialysis for 2 h at 37°C. 2 The percentage of drug unbound was 60.0% 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or a,-acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non-esterified fatty acid concentration (NEFA) (r = 0.443, P < 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 ,ug/ml theophylline.6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration-dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.