Sensitive methods to measure protein synthetic rate in vivo are required to assess changes in protein expression, especially when comparing healthy with infirm subjects. We have previously applied a ‘flooding dose’ procedure using 2H5‐phenylalanine (2H5‐phe) and 2H8‐phe isotopomers as tracers, which has proven successful in measuring albumin and fibrinogen synthesis in response to feeding in cancer patients. Using tert‐butyldimethylsilyl derivatives, we have observed that 2H7‐phe is formed with time in vivo from 2H8‐phe, probably during transamination. This increases errors when estimating the fractional synthetic rate (FSR) using the 2H8‐phe isotopomer compared with the 2H5‐phe isotopomer. We sought to improve this situation by use of an alternative derivative that overcomes this problem whilst also streamlining sample preparation. When using N‐ethoxycarbonyltrifluoroethyl (ECTFE) amino acid esters, 2H8‐phe is effectively converted into 2H7‐phe through fragmentation under electron ionisation (EI), allowing both 2H8‐phe and 2H7‐phe isotopomers to be measured as a single intense CH fragment at 98 Th. To illustrate the improved situation, the mean RMS residual was calculated for all albumin data, for each isotopomer and for each derivative. Albumin‐bound Phe was analysed as ECTFE‐phe with improved precision, independent of the isotopomer used, confirming that the new derivative is superior. Copyright © 2010 John Wiley & Sons, Ltd.