Enantioselective Interactions of Anti-Infective 8-Aminoquinoline Therapeutics with Human Monoamine Oxidases A and B

Abstract

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and -B. NPC1161B, the (R)-(−) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and -B. Racemic PQ and (R)-(−)-PQ both showed marginally greater (1.2- and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, (S)-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The (S)-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and -B compared to the (R)-(−) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics.

Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

“…The differential pharmacokinetic, metabolism and pharmacologic profiles of individual enantiomers of PQ is now well established, as evidenced in in vitro human hepatocytes and also in animals ( Fasinu et al, 2014 ; 2016 ; 2022 ; Saunders et al, 2014 ; Chaurasiya et al, 2021 ). A recent study from our group also demonstrated highly enantioselective PK and metabolism profiles in subjects treated with single dose of individual PQ enantiomers ( Khan et al, 2022a ).…”

“…With respect to metabolism, as observed in our single dose study ( Khan et al, 2022a ), plasma exposure to parent drug was significantly higher for SPQ treated groups than for RPQ, and RSPQ behaved in an additive fashion. Plasma cPQ levels were much higher after RPQ administration than SPQ, likely reflecting the greater vulnerability of RPQ to metabolism by monoamine oxidases ( Chaurasiya et al, 2021 ). This presumably also accounts for the reduced exposure to the parent drug after RPQ administration.…”