Intestinal transport and metabolism of glucose-conjugated kyotorphin and cyclic kyotorphin: metabolic degradation is crucial to intestinal absorption of peptide drugs

• Published in: Biochimica et biophysica acta Vol. 1475; no. 1; pp. 90 - 98
• Main Authors: Mizuma, Takashi, Koyanagi, Akihiro, Awazu, Shoji
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2000
• Subjects: Acetaminophen - pharmacokinetics; Animals; Biological Transport; Chromatography, High Pressure Liquid; Cyclic peptide; Endorphins - blood; Endorphins - chemistry; Endorphins - pharmacokinetics; Glucose - chemistry; Glucose conjugate; Intestinal Absorption; Intestinal Mucosa - metabolism; Kinetic analysis; Kyotorphin; Male; Metabolism; Peptide absorption; Peptides - metabolism; Peptides, Cyclic - metabolism; Pharmaceutical Preparations - metabolism; Rats; Rats, Wistar; Transport; Cyclic peptide; Glucose conjugate; Kyotorphin; Kinetic analysis; Peptide absorption; Intestinal absorption; Metabolism; Transport
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/S0304-4165(00)00051-9

Intestinal transport and metabolism of modified kyotorphin (KTP) were studied in rats. Modified KTPs studied were C-terminally modified KTP with p-aminophenyl-β- D-glucoside (KTP-pAPβglc), N-terminally modified KTP-pAPβglc with t-butyloxycarbonyl group (Boc-KTP-pAPβglc) and the N- and C-terminally modified KTP by cyclization (cyclic KTP). KTP-pAPβglc was metabolized at a similar rate to that of KTP, and did not appear on the serosal side. Although Boc-KTP-pAPβglc was also metabolized, it was more stable than KTP and appeared on the serosal side. Cyclic KTP was also quite stable and appeared on the serosal side. The modified KTPs were evaluated kinetically for absorption consisting of membrane transport and metabolism. Absorption clearance (CL abs) of cyclic KTP, Boc-KTP-pAPβglc and Boc-KTP was higher than that of KTP (0.247 μl/min/cm) (Mizuma et al., Biochim. Biophys. Acta 1335 (1997) 111–119), which is the theoretical maximum by complete inhibition of peptidase activity, indicating that derivatization of KTP increases the membrane permeability. Furthermore, the data clearly showed that the greater the metabolic clearance (CL met) of KTP and the KTP derivatives, the lower the absorption clearance (CL abs). These results and further simulation study led to the conclusion that metabolic degradation in the intestinal tissues is more critical than membrane permeability (transport) for oral delivery of peptide drugs. Based on the stability of cyclic KTP in serum, this appears to be a good candidate analgesic peptide drug.