Role of Human Liver Microsomes in In Vitro Metabolism of Drugs—A Review

Abstract

Drug metabolism studies are essential and necessary during the evaluation of drugs. This review discusses the in vitro human liver models to estimate the drug metabolic fates in vivo. Different approaches are provided and emphasis is placed on the potential of human liver microsomes for drug metabolism and inhibition studies. The methodology for these studies using human liver microsomes, applications of human liver microsomes, and the drugs studied by human liver microsomes are listed. Human liver microsomes represent a critical experimental model for the evaluation of drug metabolites with a high probability of clinical success.

Analytical Methods for Quantification of Drug Metabolites in Biological Samples

“…The disadvantage of this in vitro model is the latency of glucuronidation because the active site of UGT is shielded behind a hydrophobic barrier. To resolve this problem a pore-forming agents such as alamethicin are used [14][15][16][17][18].…”

“…A NADPH regenerating system (NRS), which consists of β-NADPH, glucose-6-phosphate and glucose-6-phosphate dehydrogenase, or NADPH is required in the incubation for the evaluation of CYP activity and uridine diphospoglucuronic acid (UDPGA) has to be added as a cofactor when evaluating UGT enzyme activity [14][15][16].…”

“…Additionally, gender-specific microsomes are available for the estimation of gender-based discrepancies in drug biotransformation. In drug discovery process HLM are used for metabolite identification, evaluation of interspecies differences in drug metabolism, prediction of in vivo clearance, reaction phenotyping and metabolic pathway identification [14][15][16][17][18]20].…”

“…In order to evaluate the UGT activity UDPGA and alamethicin (pore-forming reagent) are required [14][15][16].…”

“…This limits the expected metabolic competition and formation of some in vivo present metabolites. Another drawback is a very difficult assessment of the fraction of drug bound to plasma proteins versus to microsomes which is an important factor in the estimation of in vivo biotransformation [14][15][16]18]. …”