Effects of ABCB1, UGT1A1, and UGT1A9 Genetic Polymorphisms on the Pharmacokinetics of Sitafloxacin Granules in Healthy Subjects

Abstract

Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single-dose and multidose cohorts and the effects of ABCB1, UGT1A1, and UGT1A9 genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single-dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high-fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration-time data. The genotypes for ABCB1, UGT1A1, and UGT1A9 single-nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single-nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single-dose and multidose studies, respectively. Sitafloxacin AUC and C max increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that C max was lower in the ABCB1 (rs1045642) mutation group, whereas t 1/2 was longer in the UGT1A1 (rs2741049) and UGT1A9 (rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However, ABCB1 (rs1045642), UGT1A1 (rs2741049), and UGT1A9 (rs3832043) genetic polymorphisms are likely to influence the C max or t 1/2 and thereby merit further clinical evaluation.

Transporter and metabolizer gene polymorphisms affect fluoroquinolone pharmacokinetic parameters

“…SNPs in UGT1A9 rs2741049 and rs3832043 have a longer half-life (t 1/2 ) than those in subjects without the variant; this was thought to occur due to decreased metabolism and disposition of sitafloxacin. However, this study did not show significant changes in AUC in either the ABCB1 or UGT1A9 groups (Sun et al, 2021). Acyl glucuronidation of trovafloxacin has been studied in human liver microsomes and also in UGT isoform-expressing systems in human liver microsomes.…”

“…Polymorphism of UGT1A1 , UGT1A9 , and ABCB1 also affects the pharmacokinetic profile in sitafloxacin and trovafloxacin ( Figure 1 ; Table 2 ). A study on sitafloxacin showed that there was an association of genetic polymorphism of the human drug transporter ABCB1 rs1045642 in subjects with heterozygous or homozygous genotype variants with a lower C max of sitafloxacin than that in subjects without variants ( p < 0.05) ( Sun et al, 2021 ). SNPs in UGT1A9 rs2741049 and rs3832043 have a longer half-life (t 1/2 ) than those in subjects without the variant; this was thought to occur due to decreased metabolism and disposition of sitafloxacin.…”

“…Sitafloxacin can reduce C max by 50% when consumed by subjects who are fasting or having high fat foods intake, but it does not affect t max , t 1/2 elimination, or total exposure (AUC 0-t and AUC 0-∞ ). Despite only being possible in one dosing group of 10 participants, it is possible to affect the pharmacokinetic properties of ciprofloxacin, including t 1/2 and C max ( Sun et al, 2021 ).…”

“…Studies on sitafloxacin at rs2741049 and rs3832043 showed a significant effect on longer drug half-life t 1/2 ( p < 0.05). Inferring a poor metabolizer, rs2741049 and rs3822043 may play a part in the pharmacokinetic profile of the drug ( Sun et al, 2021 ), another study at rs3832043 showed a possible effect on acetaminophen metabolism in neonates ( Linakis et al, 2018 ). Thus, UGT1A9 may have a role in the pharmacokinetic profile of the drug.…”

“…Two studies showed in-line results in the ABCB1 gene. A decrease in AUC and an increase in T max occurred with moxifloxacin, whereas in sitafloxacin there was a decrease in C max (p < 0.05) (Naidoo et al, 2018), (Weiner et al, 2007), (Sun et al, 2021). According to the moxifloxacin pharmacokinetics results, ABCB1 rs2032582 and C3435T suggest a hyper metabolizer phenotype, while rs1045642 on sitafloxacin suggests a poor metabolizer.…”