If close control of ISF concentration is required there must either be some means to reduce or prevent changes in input or the clearance must alter. When input is from plasma one way in which changes in input can be made less sensitive to plasma concentration is for the input mechanism to be operating not too far from its maximum rate, i.e. for the substrate concentration in plasma to be well above the Km for the input mechanism. However, the same limitation may apply to efflux as to influx, with the resulting changes in ISF concentration difficult to predict (e.g. for glucose, see Fig. 14 and Appendix D).