What kinds of substrates show P-glycoprotein-dependent intestinal absorption? Comparison of verapamil with vinblastine.
The influence of P-glycoprotein (P-gp) on intestinal absorption of drugs was investigated by comparison of the uptakes of two P-gp substrates, verapamil and vinblastine, using intestinal segments of wild-type and mdr1a/1b gene-deficient (mdr1a/1b(-/-)) mice, and Caco-2 cells. When [(3)H]vinblastine was injected into intestinal segments of wild-type mice, vinblastine was absorbed from duodenum and ileum, but not from jejunum. This difference among intestinal regions could not be explained by segmental differences of mdr1a mRNA expression. In Caco-2 cells, it was found that vinblastine had a high value of efflux/influx ratio (an index of affinity for P-gp) of 12.1, and a low permeability of less than 1 x 10(-6) cm/sec. The corresponding values for verapamil were 4.9 and 10.6 x 10(-6) cm/sec, respectively. After oral administration of [(3)H]vinblastine to mice, the maximum concentration (C(max)) and the area under the plasma concentration time-curve from time 0 to 24 hr (AUC(0-24 hr)) for mdr1a/1b(-/-) mice were 1.5 times greater than those for wild-type mice, while these parameters were not significantly different between the two strains in the case of [(3)H]verapamil. Therefore, P-gp substrates may be classified into at least two types, i.e., verapamil-type, for which the intestinal absorption is unaffected by P-gp, and vinblastine-type, for which the intestinal absorption is influenced by P-gp. Vinblastine-type P-gp substrates, with low permeability and high affinity for P-gp, would be unfavorable candidates for oral drugs.
Ogihara
Takuo
T
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan. togihara@mochida.co.jp
Kamiya
Masatsugu
M
Ozawa
Makoto
M
Fujita
Takuya
T
Yamamoto
Akira
A
Yamashita
Shinji
S
Ohnishi
Shuhei
S
Isomura
Yasuo
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000983:Antipyrine / Q000494:pharmacology; D019540:Area Under Curve; D018938:Caco-2 Cells; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008353:Mannitol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014316:Tritium; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014747:Vinblastine / Q000008:administration & dosage / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D014316:Tritium; D008353:Mannitol; D014747:Vinblastine; D014700:Verapamil; D000983:Antipyrine