For the phenobarbital metabolism the binding of thiopentone in human serum is about 85% and remarkably constant over the concentration range between 4 and 80 micrograms/mL.
The higher percentage of protein binding occurs at lower plasma concentrations of thiopental In phenobarbital metabolism . The percentage binding increases with increasing pH from approximate 75% at pH 6.0 to a maximum value of 95% at pH 9.0.6 Hypoalbuminaemia may account for decreased protein binding of barbiturates in patients with cirrhosis of the liver.
The average protein bound form is reduced in patients with deteriorated kidney and liver function and also in elderly subjects, in pregnant women and in newborns. This may explain, in part, increased drug sensitivity demonstrated by patients with uremia or cirrhosis of the liver.
In phenobarbital metabolism the displacement from protein binding sites by other drugs, such as aspirin and phenylbutazone, can lead to increase in free fraction and enhanced drug effects. Methohexital readily crosses the placentain both directions.
The distribution of thiopental from blood to tissues is influenced by the state of ionization of the drug and its binding to plasma proteins. The pK of thiopental (7.6) is near blood pH.
Therefore, acidosis will favor the nonionized fraction of drug, which has greater access to the CNS because of its higher lipid solubility leading to greater effect. Cross-tolerance between alcohol and thiopental exists after regular intake even when the amount is low during phenobarbital metabolism