P-gp substrate

P-glycoprotein (P-gp) works as a transporter at the intestinal mucosa pumping drugs out into the lumen. Absorption of P-gp substrates, such as digoxin, cyclosporine, etc., can be increased by inhibitors of P-gp and reduced by inducers. 

Figure 20.2 Pharmacophore models for P-gp inhibition. A. P-gp inhibition pharmacophore aligned with the potent inhibitor LY335979. B. P-gp substrate pharmacophore aligned with verapamil. C. P-gp inhibition pharmacophore 2 aligned with LY335979. Green indicates H-bond acceptor feature, and cyan indicates hydrophobic feature. See color plate.

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

Digoxin 81 High 10 Fa calculated from urinary exretion data of p.o. and i.v. administered P-gp substrate... 

The applicability range of any model should be limited to molecules having a similar mechanism of transport. Therefore, we have selected from the literature only those compounds with well-characterized Caco-2 cell permeability and excluded compounds with a high efflux ratio. Known P-gp substrates and actively transported compounds were also excluded from the list. 

The structures of the drugs used as a small test set for the model are listed in Table 17.1. Loperamide and asimadoline are P-gp substrates terfenadine and ebastine are compounds that are rapidly metabolized alprazolam, dobazam, di-and mono-hydroxy-L66858 [11] are benzodiazepines testosterone and corticosterone are hormones and cefadroxyl, cefaclor, cephalotin and cefmetazole are cephalosporins [12]. Finally, peptides 1 to 10 are peptidomimetic drugs [13]. 

An additional example of a bioavailability-predicted absorption plot is shown for a series of calcium antagonists (Fig. 19.8). Again there is considerable scatter in the data, and the four compounds - felodipine, nisoldipine, diltiazem, and verapamil -are predicted to be much better absorbed than was actually observed. Some of these compounds are known to undergo rapid first-pass metabolic clearance, and are also P-gp inhibitors or substrates (diltiazem and felodipine are P-gp substrates nicardipine and nitrendipine are P-gp inhibitors [25] verapamil is a P-gp inhibitor), and this might contribute to the scatter obtained in the graph. 

Second, P-gp differs from other transporters in that it recognizes its substrates when dissolved in the lipid membrane [52], and not when dissolved in aqueous solution. The site of recognition and binding has been shown to be located in the membrane leaflet facing the cytosol [53, 54], This implies that the membrane concentration of the substrate, Csm, determines activation [57]. Since the nature of a molecular interaction is strongly influenced by the solvent, the lipid membrane must be taken into account as the solvent for the SAR analysis of P-gp. Under certain conditions, the effect of additional solvents or excipients (used to apply hydrophobic substrates or inhibitors) on the lipid membrane and/or on the transporter must also be considered. Lipophilicity of substrates has long been known to play an important role in P-gp-substrate interactions nevertheless, the correlation of the octanol/water partition coefficients with the concentration of half-maximum... 

It thus follows that the membrane concentration of typical P-gp substrates for halfmaximum activation of P-gp falls in the range of 1 to 10 mmole drug per mole lipid. This is a much narrower concentration range than that required for the same substances in the aqueous phase 10 8 to 10 3 M. A similar phenomenon has been observed in anesthesia. The membrane concentration of anesthetics required for anesthesia has been found to be 33 mM, independent of the anesthetic applied (Meyer-Overton rule). 

Fig. 20.4. H-bond acceptor patterns observed two electron donor groups with a spatial in P-gp substrates. Type I units patterns separation of 4.6 + 0.6 A. A denotes a informed by electron donor pairs with a spatial bonding acceptor group (electron donor...

P-gp substrates are in general either neutral or cationic at physiological pH (weak bases). Weak bases can cross the lipid membrane in the uncharged form and reprotonate in the negatively charged cytosolic leaflet of the membrane. With a few exceptions (e.g., the tetraphenyl phosphonium ion, which can reach the cytosolic membrane leaflet due to charge delocalization [70]), permanently charged cations do not cross the cell membrane and therefore cannot interact with P-gp in intact cells. They can, however, insert into the cytosolic leaflet in inside-out cellular vesicles and are then transported by P-gp [42, 71]. 

P-gp substrate 64 substrates Different sources P-gp substrates characterized by well-defined sets of H-bond acceptor elements (type I and type II units). Strength and number of H-bond [40]... 

P-gp substrate 76 substrates and 32 substrates and 53% substrates and Different sources Ensemble of pharma- [43]... 

P-gp substrate 63 substrates and 35 substrates and 94% substrates and Transport MDR1-MDCK High probability to be a [50]... 

Overall accuracy 86% with zero hydrogen atoms and high number of the O-C hydrides. P-gp substrate showed MolES > 110 ... 

P-gp substrate 116 substrates and 85 nonsubstrates 19 substrates and 6 nonsubstrates 84.2% substrates and 66.7% nonsubstrates correctly predicted. Overall accuracy 86%... 

P-gp substrate and inhibitor 95 substrates, 78 inhibitors and 32 overlapping 83.3% substrates and 80.8% inhibitors correctly predicted... 

P-gp substrate 109 compounds 20 compounds Predicted values in good agreement with experimental data... 

P-gp substrate 22 substrates and 31 nonsubstrates 115 substrates and 157 nonsubstrates 61% substrates and 81% nonsubstrates correctly predicted. Overall accuracy 72.4% Transport Caco-2 cell line Size, shape (e.g. molecular surface and glo-bularity), hydrophilic and H-bonding related descriptors correlated positively with P-gp activity, log P0/w not significant [54]... 

P-gp substrate 9 substrates and 69 substrates and 88.4% substrates Transport and Caco-2 (transport) Pharmacophore (sub- [54]... 

In our group, we developed a computational model for discriminating P-gp substrates from nonsubstrates, based on Caco-2 ER values [54], A partial least... 

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