Racial Disparity in Drug Disposition in the Digestive Tract

Abstract

The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.

Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety

“…To our knowledge, this is the first work to describe a higher amlodipine exposure and t max in Latin-Americans and healthy volunteers with other races compared to Caucasians. However, pharmacokinetic differences are well known for several drugs according to race [ 29 ], which are believed to be due to the different allele frequency in the CYP P450 genes and other genes involved in drug transport and metabolism among races [ 30 , 31 ]. These genetic differences among races, along with the high incidence of diseases that increases the risk of pharmacological interactions and ADRs, such as diabetes or chronic kidney disease, might lead to different management of antihypertensive treatment in the Latin-American population [ 32 , 33 ].…”

Comparison of outcomes following intravenous magnesium compared with intravenous labetalol and oral nifedipine in 355 pregnant Han Chinese women with preeclampsia

“…The drugs that have high first-pass metabolism and high plasma protein binding exhibit racially diverse responses. [20] Intravenous magnesium sulfate provides a primary reduction of blood pressure in Han Chinese women with preeclampsia.…”

Pharmacokinetics and Bioequivalence of 2 Safinamide Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions

“…It seems the absorption of safinamide was more rapid in Chinese volunteers than other races. Some studies reported that Asian populations are expected to have a higher probability of low breast cancer resistance protein efflux function in the gastrointestinal tract, 17,18 which might explain this difference above.…”