Evaluation of a targeted prodrug strategy to enhance oral absorption of poorly water-soluble compounds

• Published in: Pharmaceutical research Vol. 15; no. 7; pp. 1012 - 1018
• Main Authors: CHAN, O. H, SCHMID, H. L, STILGENBAUER, L. A, HOWSON, W, HORWELL, D. C, STEWART, B. H
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01-07-1998; Springer Nature B.V
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Cell Membrane Permeability; Chemical Phenomena; Chemistry, Physical; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Mucosa - metabolism; Intestines - ultrastructure; Male; Medical sciences; Microvilli - enzymology; Neurokinin-1 Receptor Antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Rats, Wistar; Solubility; Water; Intravenous administration; Targeting; Rat; Digestive system; Rodentia; Gut; Solubility; Oral administration; Bioavailability; Permeability; Prodrug; In vitro; In vivo; Vertebrata; Mammalia; Absorption; Animal; Intraduodenal administration; Antagonist; Tachykinin receptor; Pharmacokinetics; Physicochemical properties
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1011969808907

The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound.
Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose.
Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug.
Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.