For instance, a single-dose study of a CR formulation of buspirone (5-hydroxytryptamine 1A (5-HT) partial agonist) showed a relative bioavailability of 170–190% as compared PD0332991 to a similar dose of an IR formulation (Sakr and Andheria, 2001b) producing an almost 3.3-fold higher exposure at steady-state (Sakr and Andheria, 2001a). For oxybutynin (anticholinergic), the CR formulation displayed a relative bioavailability of 153% as compared to the IR formulation (Gupta and Sathyan, 1999). Additional studies have showed that the CR formulation of oxybutynin significantly reduced the anticholinergic side-effects of oxybutynin

as compared to the IR formulation, without reducing the efficacy of oxybutynin for the treatment of urinary incontinency (Comer and Goa, 2000, Gupta et al., 1999 and Sathyan et al., 2001). Despite almost complete absorption, both buspirone and oxybutynin display an oral bioavailability of around 4% and 6%, respectively, due to extensive first-pass metabolism in

the gut wall and liver (Douchamps et al., 1988, Gammans et al., 1985, Lukkari et al., 1998, Mizushima et al., 2007, Yaich et al., 1998 and Zhu et al., 2005). Cytochrome P450 (CYP) 3A4 is believed to be the main buy GW3965 enzyme responsible for the metabolism of oxybutynin and buspirone (Douchamps et al., 1988, Gammans et al., 1985, Lukkari et al., 1998, Mizushima et al., 2007, Yaich et al., 1998 and Zhu et al., 2005). Therefore it has been hypothesized that the observed differences between CR and IR formulations are a consequence of the distribution pattern of CYP3A along the small intestine (Gupta and Sathyan, 1999, Sakr and Andheria, 2001a and Sakr

and Andheria, 2001b; Tubic-Grozdanis et al., 2008). The abundance of CYP3A varies along the membrane of the small intestine, being higher in the upper region and decreasing towards the distal region and colon (Berggren et al., 2007, Paine et al., 1997 and Zhang et al., 1999). Therefore, the CR formulation also of such drugs would release most of its drug content into intestinal regions with a lower abundance of CYP3A, thus potentially bypassing the CYP3A-mediated first pass metabolism. This hypothesis is supported by an observed reduction in the exposure of the metabolites of both buspirone and oxybutynin when administered as a CR formulation vs. their IR formulations (Gupta and Sathyan, 1999, Sakr and Andheria, 2001a and Sakr and Andheria, 2001b). The reduction in exposure of oxybutynin’s metabolite, N-desethyloxybutynin, could also explain the reported improvements in the safety profile of oxybutynin when formulated as a CR (Gupta et al., 1999 and Sathyan et al., 2001). Despite the fact that clinical evidence might support the aforementioned hypothesis, there are no clear indications whether this higher relative bioavailability would be observable for all CYP3A substrates when formulated as CR.