title: Oral coadministration of β-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation.
abstract: Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with β-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by β-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed.
authors.affiliation: Janssen Research & Development, LLC, a Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Drug Safety Sciences, Raritan, New Jersey 08869, USA. geichenb@its.jnj.com
authors.forename: Gary
authors.initials: G
authors.lastname: Eichenbaum
authors.forename: C-P
authors.initials: CP
authors.lastname: Hsu
authors.forename: Vangala
authors.initials: V
authors.lastname: Subrahmanyam
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Robert W
authors.initials: RW
authors.lastname: Tuman
authors.forename: Dana L
authors.initials: DL
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D005966:Glucuronidase / Q000008:administration & dosage* / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D007189:Indans / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: C505208:(6,7-dimethoxy-2,4-dihydroindeno(1,2-c)pyrazol-3-yl)(3-fluorophenyl)amine; D020719:Glucuronides; D007189:Indans; D011720:Pyrazoles; D017479:Receptors, Platelet-Derived Growth Factor; D005966:Glucuronidase