Enantiospecific determination of naftopidil by RRLC–MS/MS reveals stereoselective pharmacokinetics and tissue distributions in rats

In Vitro Effects of Plasma Collected From Rats Administered Naftopidil on Whole Urinary Bladder Preparation Isolated From Rats

“…These effects presumably could be attributed to either of 2 mechanisms: the presence of naftopidil itself in the plasma, and naftopidil-induced changes in the plasma levels of monoamines and amino acids. With regard to the first mechanism, the elimination half-life (t1/2) of naftopidil is 12-15 hours after a single dose of 20 mg/kg in rats [17]. In the present study, naftopidil was administered QD for 14 days as an oral dose at 5 mg/rat/ day, which is equivalent to a dose of approximately 20-25 mg/ kg/day.…”

A prospective randomized controlled study on the Suppression of Prostate Cancer by Naftopidil (SNAP)

“…Non-human studies also indicate its anti-proliferative effect on multiple cancer cells in vitro or in vivo in mice [10,16]. It is fortunate that naftopidil distributes preferentially in the prostate; the intra-prostatic concentration after an oral dose of 20 mg/kg in rats reached 50-100 µg/g (1-24 hours), which was highest among all organs studied [17]. These concentrations are equivalent to 128-256 µM, given the molecular weight of naftopidil (392) and a conversion rate of 1 g = 1 ml.…”

Stereoselective Tissue Distribution of Ketolorac in Rats – Differential Uptake of Ketolorac Enantiomers in Certain Tissues

“…The bioavailability of naftopidil after intra-gastric administration in rats favored the (S)-(-)-enantiomer of naftopidil which showed a 2-fold higher bioavailability as compared to the (R)-( + )-enantiomer [5]. However, examination of the tissue distribution and pharmacokinetics for the 2 enantiomers of naftopidil revealed a contrasting picture to that seen in plasma; in all 3 tissues examined, namely: the prostrate, liver and kidney, the bioavailability of the (R)-( + )-naftopidil was greater than that of the (S)-(-)-enantiomer and the corresponding (R)-( + )/(S)-(-) ratios were 3.16, 1.33 and 2.90, respectively, in the 3 tissues [5]. In summary the interesting published data of tissue pharmacokinetics of ketolorac enantiomers when put in context to the earlier reported stereoselective pharmacokinetic data of ketolorac demonstrated the local uptake of ketolorac enantiomers into various tissues may be under the influence of uptake transporters present in the tissues and therefore it is erroneous to assume that the stereoselectivity observed in the plasma will remain the same in the tissues for the racemic drugs.…”

“…Since the elimination of ketolorac is governed by both renal and non-renal mechanisms in the rat [4], the observed stereoselectivity in the plasma may be partly explained by the faster renal excretion of the S-ketolorac as compared to that of the R-enantiomer. A recently published tissue and plasma pharmacokinetic data of the enantiomers of naftopidil highlights the importance of simultaneous measurements of the plasma and tissue levels [5]. The bioavailability of naftopidil after intra-gastric administration in rats favored the (S)-(-)-enantiomer of naftopidil which showed a 2-fold higher bioavailability as compared to the (R)-( + )-enantiomer [5].…”

“…A recently published tissue and plasma pharmacokinetic data of the enantiomers of naftopidil highlights the importance of simultaneous measurements of the plasma and tissue levels [5]. The bioavailability of naftopidil after intra-gastric administration in rats favored the (S)-(-)-enantiomer of naftopidil which showed a 2-fold higher bioavailability as compared to the (R)-( + )-enantiomer [5]. However, examination of the tissue distribution and pharmacokinetics for the 2 enantiomers of naftopidil revealed a contrasting picture to that seen in plasma; in all 3 tissues examined, namely: the prostrate, liver and kidney, the bioavailability of the (R)-( + )-naftopidil was greater than that of the (S)-(-)-enantiomer and the corresponding (R)-( + )/(S)-(-) ratios were 3.16, 1.33 and 2.90, respectively, in the 3 tissues [5].…”