The hepatic extraction fraction and maximum excretory rate of conjugated cholate are greater than those of free cholate (studied after acute taurine depletion); the possibility that this difference might be due to greater bile-to-blood back-diffusion of un-ionized cholic acid (pKa 5-5) compared to that of taurocholic acid (pKa 2) has been investigated by varying the pH of bile by secretin or acetazolamide administration in the anaesthetized dog. 2. The mean biliary pH during free cholate excretion in the control state in twenty-three experiments was 7-5 (at which approximately 1% of cholate is un-ionized). Three to fourfold changes in the hydrogen ion activity of bile (which resulted in changes of the same magnitude in the percentage of un-ionized cholic acid) had no significant effect on the total (mainly free) cholate maximum excretory rate. It is concluded that back-diffusion of un-ionized cholic acid in the bile ducts is not an important determinant of the secretory performance of free cholate. 3. The bile flow rate associated with mainly free cholate excretion is much higher than that associated with taurocholate excretion at the same rate; the extra bile flow appears to arise largely by means that are independent of the osmotic effect of cholate excretion, as the osmotic coefficient (osmolality/total solute concentration) of bile containing mainly free free cholate (calculated directly) was only slightly greater than that of bile containing mainly taurocholate (obtained by extrapolation) at the same total cholate concentration. 4. The peak hepatic excretory rate of taurocholate following the instillation of the entire contents of the gall-bladder of a fasted dog into the distal ileum was only about one fifth of the maximum rate attainable; at the peak rate taurocholate is almost completely removed in the first passage of blood through the liver.
