The effect of ABCB1 polymorphism on the pharmacokinetics of saquinavir alone and in combination with ritonavir.
This genotype panel study investigated the effect of ABCB1 polymorphism in exon 26 (C3435T), exon 21 (G2677T/A), and exon 12 (C1236T) on saquinavir pharmacokinetics and on the expression and activity of P-glycoprotein (P-gp) in peripheral blood monocytic cells (PBMCs). One hundred and fifty healthy volunteers were genotyped to identify 15 TT3435 and 15 CC3435 individuals. In these individuals, saquinavir pharmacokinetics were assessed after administration of a single oral dose of saquinavir 1,000 mg and saquinavir/ritonavir 1,000/100 mg. PBMC P-gp expression and activity were assessed in 15 and 19 subjects. The co-administration of ritonavir on study day 2 caused a significant increase in saquinavir exposure, in both TT3435 and CC3435 individuals. No correlation was observed between the ABCB1 C3435T, G2677T/A, and C1236T polymorphisms, separately and in haplotypes, with saquinavir pharmacokinetics, administered with or without ritonavir and with PBMC P-gp expression and activity. In conclusion, ABCB1 polymorphism has no pronounced effect on saquinavir exposure.
la Porte
C J L
CJ
Division of Infectious Diseases, The Ottawa Health Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada. claporte@ohri.ca
Li
Y
Y
Béïque
L
L
Foster
B C
BC
Chauhan
B
B
Garber
G E
GE
Cameron
D W
DW
van Heeswijk
R P G
RP
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D004338:Drug Combinations; D005091:Exons; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006239:Haplotypes; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008137:Longitudinal Studies; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D020112:Rhodamine 123 / Q000378:metabolism; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D020112:Rhodamine 123; D019258:Saquinavir; D019438:Ritonavir