Characterization of efflux transport of the PDE5 inhibitors, vardenafil and sildenafil

Choi, Min‐Koo; Song, Im‐Sook

doi:10.1111/j.2042-7158.2012.01498.x

Cited by 34 publications

(27 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1, 2). Because it has been reported that sildenafil is a substrate for P-gp, 8) it was used as a positive control in the present study. In LLC-PK 1 cells, the transport of sildenafil and tadalafil in both directions was increased periodically over 120 min (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Choi and Song 8) demonstrated that efflux transporters were involved in the mechanisms for the transcellular transport of sildenafil across Caco-2 cell monolayers. That is, the B to A transport of sildenafil was 8.81-fold greater than the A to B transport, suggesting limited intestinal absorption due to the efflux transporter-mediated secretion of sildenafil.…”

Section: Discussionmentioning

confidence: 99%

“…To compensate for the volume sampled, an 80-µL (apical side) or a 150-µL (basal side) aliquot of incubation medium pre-warmed at 37°C was added immediately after each sampling. The concentrations of sildenafil and tadalafil in each sample were determined by LC-MS/MS 8,12) and HPLC methods, 7) respectively. When kinetic parameters of the membrane permeation of sildenafil or tadalafil in LLC-GA5-COL150 cells were estimated, mannitol was used as a paracellular marker.…”

Section: )mentioning

confidence: 99%

“…Mass spectra were recorded by electrospray ionization in the positive mode. The detector was operated in selected reaction monitoring (SRM) mode using the transitions of sildenafil at m/z 475.4 283.0 8) and diazepam at m/z 285.0 193.0, 12) respectively. The peak areas were calculated using Qualbrowser software (Thermo Fisher Scientific).…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

“…7) That is, the Michaelis-Menten constant (K m ) values for CYP3A4 and CYP3A5 isoforms were estimated to be 27.7±7.5 and 17.4±3.2 µM, respectively, and the maximum transport rate (V max ) values were 30.7±11.3 and 18.9±6.1 pmol/min/pmol P450, respectively. 7) In addition, Choi and Song 8) reported that sildenafil was a substrate for P-glycoprotein (P-gp). That is, the transcellular transport of sildenafil in P-gp-expressing Madin-Darby canine kidney II (MDCKII)-multidrug resistance protein 1 (MDR1) cells in a basal to apical (B to A) direction was 4.87-fold greater than that from A to B.…”

mentioning

confidence: 99%

See 4 more Smart Citations

<i>In Vitro</i> P-Glycoprotein-Mediated Transport of Tadalafil: A Comparison with Sildenafil

Higashi

Watanabe

Tamura

et al. 2017

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Tadalafil and sildenafil are selective inhibitors of phosphodiesterase type 5, showing marked pharmacokinetic variability in patients with pulmonary arterial hypertension. It has been reported that sildenafil is a substrate for P-glycoprotein (P-gp), but whether tadalafil is a substrate for P-gp remains to be determined. The objective of the present study was to elucidate whether tadalafil is a substrate for P-gp. Transcellular transport of sildenafil and tadalafil (5 µM each) was examined using renal epithelial LLC-PK 1 and P-gpexpressing LLC-GA5-COL150 cell monolayers. The efflux ratio of the basal to apical (B to A) transport of sildenafil to the A to B transport after 120-min incubation in LLC-GA5-COL150 cells (1.52) was significantly higher than that in LLC-PK 1 cells (0.711). The efflux ratio of the B to A transport of tadalafil to the A to B transport after 120-min incubation in LLC-GA5-COL150 cells (10.4) was significantly higher than that in LLC-PK 1 cells (1.23). In LLC-GA5-COL150 cell monolayers, the V max and K m values of sildenafil transport calculated from a modified Michaelis-Menten equation were 101 64 pmol/min/cm 2 and 112 47 µM, respectively. On the other hand, those of tadalafil transport were 13.6 4.8 pmol/min/cm 2 and 22.7 9.3 µM, respectively. In the presence of a P-gp inhibitor (PSC833), the B to A transport of tadalafil was decreased by 28.6% in LLC-GA5-COL150 cells, and the A to B transport of tadalafil was 6.59-fold greater than that in its absence. These results indicate that tadalafil is a substrate for P-gp.Key words tadalafil; sildenafil; P-glycoprotein Tadalafil and sildenafil are potent and selective inhibitors of cyclic GMP-specific phosphodiesterase type 5 (PDE5) in vascular smooth muscle.1) These drugs have been used as treatments not only for erectile dysfunction, but also for pulmonary arterial hypertension (PAH).2) Sildenafil has a short half-life of about 3-5 h, 3) whereas tadalafil has a long half-life of about 17.5 h.4) Due to its long half-life, tadalafil has the advantage of once-a-day dosing compared with 3-times-a-day dosing for sildenafil. 5) For patient convenience and compliance, the transition from sildenafil to tadalafil has been tried in stable patients with PAH. 5) However, it is necessary to understand the difference between the pharmacokinetics of the two drugs for their safe use.Sildenafil is eliminated predominantly by hepatic metabolism and converted to an active metabolite, N-desmethyl sildenafil.6) In healthy men, metabolites are predominantly excreted into the feces (73-83%) and to a lesser extent urine (6-15%) after an oral dose.6) In our previous study, we confirmed that the N-demethylation of sildenafil was mediated by both CYP3A4 and CYP3A5 isoforms. 7) That is, the Michaelis-Menten constant (K m ) values for CYP3A4 and CYP3A5 isoforms were estimated to be 27.7±7.5 and 17.4±3.2 µM, respectively, and the maximum transport rate (V max ) values were 30.7±11.3 and 18.9±6.1 pmol/min/pmol P450, respectively.7) In addition, Choi and Song 8)reported that s...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%