Expandable macro with loops and advanced string functions?

This is easy enough using expl3 (there are several possible approaches):

\documentclass{article}
\usepackage{expl3,xparse}
\ExplSyntaxOn
\DeclareExpandableDocumentCommand \mycmd { m }
  {
    \__mycmd_loop:nN {#1} aeiouAEIOU \q_recursion_tail \q_recursion_stop
  }
\cs_new:Npn \__mycmd_loop:nN #1#2
  {
    \quark_if_recursion_tail_stop_do:nn {#2} { a }
    \tl_if_head_eq_charcode:nNT {#1} #2
      {
        \use_i_delimit_by_q_recursion_stop:nw { an }
      }
    \__mycmd_loop:nN {#1}
  }
\ExplSyntaxOff
\usepackage{mfirstuc}
\begin{document}

  \mycmd{somestring}                % should print "a "
  \emakefirstuc{\mycmd{sometext}}    % should print "A "
  \mycmd{otherstring}               % should print "an "
  \emakefirstuc{\mycmd{otherstring}} % should print "An "
\end{document}

As \makefirstuc does no expansion, I've had to use the e version. I'd probably prefer to get around that by using the expandable (and Unicode-aware) \text_titlecase:n:

\documentclass{article}
\usepackage{expl3,xparse}
\ExplSyntaxOn
\DeclareExpandableDocumentCommand \mycmd { m }
  {
    \__mycmd_loop:nN {#1} aeiouAEIOU \q_recursion_tail \q_recursion_stop
  }
\cs_new:Npn \__mycmd_loop:nN #1#2
  {
    \quark_if_recursion_tail_stop_do:nn {#2} { a }
    \tl_if_head_eq_charcode:nNT {#1} #2
      {
        \use_i_delimit_by_q_recursion_stop:nw { an }
      }
    \__mycmd_loop:nN {#1}
  }
\cs_new_eq:NN \Mymakefirstuc \text_uppercase:n
\ExplSyntaxOff
\begin{document}

  \mycmd{somestring}                % should print "a "
  \Mymakefirstuc{\mycmd{sometext}}    % should print "A "
  \mycmd{otherstring}               % should print "an "
  \Mymakefirstuc{\mycmd{otherstring}} % should print "An "
\end{document}

Depending on the number of cases, it might be desirable to lowercase all of the input first

\DeclareExpandableDocumentCommand \mycmd { m }
  {
    \exp_args:Nf \__mycmd:n { \text_lowercase:n {#1} }
  }
\cs_new:Npn \__mycmd:n #1
  {
    \__mycmd_loop:nN {#1} aeiou \q_recursion_tail \q_recursion_stop
  }

Here's an approach with expl3

\documentclass{article}
\usepackage{xparse,glossaries}

\ExplSyntaxOn
\DeclareExpandableDocumentCommand{\indef}{m}
 {
  \str_case_x:nnF { \tl_head:f { \tl_lower_case:n { #1 } } }
   {
    {a}{an}
    {e}{an}
    {i}{an}
    {o}{an}
    {u}{an}
  }
  {a}~#1
 }
\ExplSyntaxOff

\begin{document}

\indef{abc} --- \indef{cde} --- \indef{ABC} --- \indef{CDE}

\emakefirstuc{\indef{abc}} --- \emakefirstuc{\indef{cde}} ---
\emakefirstuc{\indef{ABC}} --- \emakefirstuc{\indef{CDE}}

\end{document}

Here's a LuaLaTeX-based solution. It defines two fully-expandable "wrapper" macros named \mycmd and \mkfirstuc, which pass their arguments to Lua functions named mycmd and mkfirstuc. The Lua functions perform the actual work of prefixing "an " or "a " to a string and of upper-casing the first character in the string, respectively.

% !TEX TS-program = lualatex
\documentclass{article}

%% Lua-side code
\usepackage{luacode}
\begin{luacode}
function mycmd ( s )
  if string.match ( string.sub(s,1,1) , "[aeiouAEIOU]" ) then
    return tex.sprint ("an " .. s)
  else
    return tex.sprint ("a " .. s)
  end
end
function mkfirstuc ( s )
  return tex.sprint ( string.upper(string.sub(s,1,1)) .. string.sub(s,2) )
end
\end{luacode}

%% TeX-side code
\newcommand\mycmd[1]{\directlua{mycmd(\luastring{#1})}}
\newcommand\mkfirstuc[1]{\directlua{mkfirstuc(\luastring{#1})}}

\begin{document}
\mycmd{abc}, \mycmd{def}, \mycmd{ABC}, \mycmd{DEF}.

\mkfirstuc{\mycmd{abc}}, \mkfirstuc{\mycmd{def}}, 
\mkfirstuc{\mycmd{ABC}}, \mkfirstuc{\mycmd{DEF}}. 
\end{document}