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1. Normal subjects showed an average increase in serum ionized calcium (Ca2+) concentration of 0·11 mmol/l in peripheral venous blood 10 min after onset of bicycle exercise at 70% of maximum aerobic capacity. The corresponding mean rise in serum total calcium concentration was 0·21 mmol/l. 2. The change in serum Ca2+ as result of acidification was studied in 20 normal subjects by carbon dioxide equilibration in vitro followed by measurement of serum Ca2+. The log serum Ca2+ was inversely proportional to serum pH. 3. The Δlog serum Ca2+/ΔpH in vitro was similar to the Δlog serum Caa+/ΔpH in vivo during exercise, this ratio, however, being somewhat greater during the first minute of exercise. 4. Serum Ca2+ returned to normal values about 20 min after stopping exercise as the pH returned to normal, but the fall immediately after stopping exercise was more pronounced than that due to the change in pH, as predicted from the studies in vitro. 5. Blood lactate concentration rose from 0·86 to 8·41 mmol/l after 10 min exercise, but the rise in blood lactate during exercise was slower than the rise in serum Ca2+. Also the fall during the recovery period was delayed compared with the fall in serum Ca2+. 6. It is suggested that the rise in serum Ca2+ during severe muscular exercise might be important for the physiological adaptations during work, and for bone metabolism.

This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.