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We have isolated and characterized a novel human and rat organic anion transporter subtype, OATP-D. The isolated cDNA from human brain encodes a polypeptide of 710 amino acids ([M.sub.r] 76,534) with 12 predicted transmembrane domains. The rat clone encodes 710 amino acids ([M.sub.r] 76,821) with 97.6% amino acid sequence homology with human OATP-D. Human and rat OATP-D have moderate amino acid sequence homology with LST-1/rlst-1, the rat oatp family, the prostaglandin transporter, and moat1/ MOAT1/KIAA0880/OATP-B. Phylogenetic tree analysis revealed that OATP-D is branched in a different position from all known organic anion transporters. OATP-D transports prostaglandin [E.sub.1] ([K.sub.m] 48.5 nM), prostaglandin [E.sub.2] ([K.sub.m] 55.5 nM), and prostaglandin [F.sub.2[alpha]], suggesting that, functionally, OATP-D encodes a protein that has similar characteristics to those of the prostaglandin transporter. Rat OATP-D also transports prostaglandins. The expression pattern of OATP-D mRNA was abundant mainly in the heart, testis, brain, and some cancer cells. Immunohistochemical analysis further revealed that rat OATP-D is widely expressed in the vascular, renal, and reproductive system at the protein level. These results suggest that OATP-D plays an important role in translocating prostaglandins in specialized tissues and cells. prostaglandin transporter; eicosanoid

Vitamin C (L-ascorbic acid) is required for certain enzymatic reactions. Two L-ascorbic acid transporters, SVCT1 and SVCT2 have been isolated from rate complementary DNA libraries to study the importance of L-ascorbic acid transport in supply and metabolism regulation of vitamin C. Both transporters mediate high affinity L-ascorbic acid transport driven by the Na+ electrochemical gradient.

The selective inhibition of hepatic cholesterol synthesis by pravastatin, an inhibitor of the hydrophilic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, was investigated. Pravastatin uptake by isolated rat hepatocytes was evaluated to test the possibility of the existence of a specific uptake mechanism for pravastatin in the liver. The results showed that a Na+ -independent, carrier-mediated active transport mechanism is involved in pravastatin uptake. This could account for the in vivo selective inhibition of hepatic cholesterol synthesis by pravastatin.

The antisense oligonucleotides (AONs) targeting the gene of each oatp subtype with subtype-specific sequences are selected, by using a gene alignment program (GAP) and antisense in vitro selection (AIVS), to compare both procedures to search for antisense sequences. The result shows the use of AONs to elucidate the mechanism of target genes related to diseases such as cancer, inflammation, and diabetes.

1. The biotransformation and disposition of tivantinib in humans, dogs and rats was examined after a single oral administration of [14C]tivantinib. Tivantinib constituted no more than one-third of the plasma radioactivity in all species, demonstrating significant contribution of the metabolites to plasma radioactivity. The major circulating metabolites in all species were M4 and M5, hydroxylated metabolites at the benzyl position of the tricyclic ring, accounting for 19.3 and 12.2% of the AUC of the total radioactivity, respectively, in humans. 2. The majority of radioactivity was excreted to the feces via bile. Tivantinib was detected at trace levels in urine, feces and bile, demonstrating extensive metabolism prior to biliary excretion and nearly complete tivantinib absorption under fed conditions. 3. Seven metabolic pathways were identified for tivantinib and included six oxidations (M4, M5, M7, M8, M9 and M11) and one glucuronidation (M23). The major metabolic and excretory pathways were found to be common among all species. Species differences in the metabolic pathways included lactam metabolite (M8) formation in humans and dehydrogenated metabolite (M11) formation in animals. 4. None of the metabolites identified in this work are believed to significantly impact the efficacy or toxicity of tivantinib in humans. [ABSTRACT FROM AUTHOR]