Prediction of Oral Absorption of Anionic Drugs that are Absorbed by the Monocarboxylic Acid Transport System

测定了卡比西林（carbenicillin， CBPC）和卡比西林（caridacillin， CIPC）在Caco-2细胞单分子膜上从尖向基的跨细胞转运。由于CBPC从肠道吸收较差，因此可以肠外使用，而CIPC是CBPC的前药，可以口服。在Transwell培养基上培养Caco-2细胞，在顶端pH=6.0、底部pH=7.4条件下测定Caco-2细胞的转运能力。CIPC通过Caco-2细胞单层的通透性约为CBPC的40倍，表明CIPC通过肠上皮细胞的运输速度更快，从而促进了CIPC的吸收。此外，研究表明，CIPC而不是CBPC是由位于上皮细胞的单羧酸运输系统运输的。从CBPC到CIPC的化学结构的修饰可能确实导致了对转运系统的更大亲和力，这反过来又导致了对前药的更大吸收。测定氯西林（MCIPC）、双氯西林（MDIPC）、苯乙西林（PEPC）、苯氧苄青霉素（PCV）和丙青霉素（PPPC）通过Caco-2细胞单层的转运情况。这些药物的渗透性范围为0.8 ~ 1.0 × 10^<-6> cm/s。如果我们假设这些药物仅通过被动扩散被吸收，口服给药后的吸收程度应为剂量的10-20% （s.b chong等人，药学研究中心）。13: 120-123, 1996)。然而，这些药物在人体的口服吸收程度为45-86%，这远远大于假设被动扩散的预测。结果表明，由于这些药物具有羧酸部分，并且在生理ph下以单阴离子形式存在，因此在这些药物的吸收过程中可能存在一个转运系统，最有可能是单羧酸转运系统。此外，在我们之前的研究中，已经证明这些药物与单羧酸转运系统具有亲和力。

Transcellular transport of carbenicillin (CBPC) and caridacillin (CIPC) through Caco-2 cell monolayer in the apical to basal direction was measured. CBPC is used pareterally because of poor absorption from the intestine, whereas CIPC is a prodrug of CBPC and is orally administered. Caco-2 cells were cultured on Transwell and the transport was measured at apical pH=6.0 and basal pH=7.4. Permeability of CIPC through Caco-2 cell monolayer was ca. 40-fold greater than that of CBPC, indicating that improved absorption of CIPC is due to much faster transport through the intestinal epithelial cells. Moreover, it was shown that CIPC, not CBPC, was transported by the monocarboxylic acid transport system that is located at the epithelial cells. It is probably true that modification of chemical structure from CBPC to CIPC resulted in much greater affinity to the transport system, which in turn resulted in greater absorption of the prodrug.Transport of cloxacillin (MCIPC), dicloxacillin (MDIPC), phenethicillin (PEPC), phenoxymethylpenicillin (PCV) and propicillin (PPPC) through Caco-2 cell monolayer was measured. Permeability of these drugs ranged from 0.8 to 1.0 x 10^<-6> cm/s. If we assume that these drugs are absorbed only by passive diffusion, extent of absorption after oral administration should be 10-20% of the dose (S.Chong et al., Pharm.Res.13 : 120-123, 1996). However, extent of oral absorption of these drugs in humans is 45-86%, which is much greater than that predicted assuming passive diffusion. The results suggest that a transport system, most probably the monocarboxylic acid transport system, is involved in the absorption of these drugs since these drugs have a carboxylic acid moiety and exist as mono-anion at physiological pH.Moreover, in our previous study, it was demonstrated that these drugs have affinity to the monocarboxylic acid transport system.