Based on PBPK principles and the ADME properties of pravastatin, what would you

Question

Based on PBPK principles and the ADME properties of pravastatin, what would you expect the effects of: (i) A polymorphism with hepatic uptake transporters that decreases their activity, (ii) drug-drug interaction due to the coadministration of another compound that inhibits canalicular transport of pravastatin into bile, (iii) drug-drug interaction due to the coadministration of another compound that inhibits pravastatin metabolism. Consider both effects on (i) pharmacological, and (ii) toxicological effects of pravastatin.

Explanation / Answer

Ans (i) The following hepatic pravastatin uptake transporters are involved, Major or important transporters: organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, multidrug resistance-associated protein 2 [MRP2 (ABCC2)], single nucleotide polymorphism in these two receptors showed varied or high variability in pharmacokinetic data for pravastatin

Minor or less important transporters: OATP2B1, organic anion transporter 3 (OAT3), bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). OATP1B1 (for hepatic uptake) and MRP2 (biliary excretion)

However many studies are done on SLCO1B1, MRP2 (ABCC2) because they are the major receptors for pravastatin and this statin has not showed any significant difference in the metabolism with respect to polymorphism in the receptors.

For SLCO1B1 three SNP haplotypes exist *1b, *5 and *15: In one study no significant differences observed in the above haplotypes with respect to pravastatin uptake or excretion pharmacokinetics..

Ans (ii): MRP2 receptor is involved in biliary excretion. Competitive binding of this receptor by another drug may result in inhibition of pravastatin excretion, however pharmacokinetic studies have shown that pravastatin is found to be not competitively inhibited with other drugs compared to other statins.

Ans (iii) Pravastatin is not significantly affected by the presence of other drug, hence it should be the statin of choice

Pharmacologicallu pravastatin being hydrophilic can be rapidly excreted without toxic effects, hence less toxic compared to other statins. Its been reported that pravastatins having inhibitory effects on natural killer cells, moderately reduced kidney functional loss. Transaminase activity slightly increased

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