The protracted development associated with lovastatin prompted the search for another statin-derived fermentation product. The intact lovastatin lactone was limited by its relatively poor oral bioavailability in patients (12-20%), so alternatives were needed. Simvastatin 3 (Figure 7) was the second entrant to the statin market and contains two additional methyl groups retaining the methyl group found in the decalin ring of lovastatin while having an extra methyl moiety in the butyrate ester group. The intact simvastatin lactone has a much higher (> 80%) overall oral bioavailability than lovastatin. Both lovastatin and simvastatin were developed as hydrophobic lactones as they offered the initial advantages of passive transport across the hepatocyte membranes, facile metabolic conversion to the biochemically active hydroxy-acids, and subsequent selective accumulation in the liver, while the corresponding hydroxy-acids provided a significantly reduced oral pharmacokinetic profile.62 Simvastatin 3 was approved in 1988 and was the first generic statin to be approved as an over-the-counter medication in the UK. Over-the-counter use of statins in the US has not been approved.

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