Mar 122012

We have added to our extensive selection of metabolism and related →ADME/DMPK services new assays for conjugation metabolism analysis (also known as phase II metabolism). Conjugation metabolism, in addition to the redox metabolism (phase I metabolism, mainly by CYP P450 enzymes) forms the major biotransformation machinery of endogenous and xenobiotic (drug) compounds.

The importance of studying the conjugation metabolism is also added to the very recent (Feb-2012) FDA Draft Guidance → Guidance for Industry: Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, 2012.

Whilst the →phase I metabolism analytics (CYP identification, inhibition, induction, suppression) is currently routinely done in drug discovery programs, good scientific expertise in phase II conjugation metabolism is much less commonly available.

We are offering a spectrum of analytics and scientific expertise in phase II conjugation metabolism

We have started with the most common conjugation metabolism enzymes, the UGTs (Uridine 5′-diphospho-glucuronosyltransferases) with our recent staffings and the currently available analytical assays include:

1) UGT-Pilot – General assessment of glucuronidation for the drug compounds

This study is devised to detect if glucuronidation happens for the studied compounds as part of its biotransformation. It does not pinpoint which UGT enzyme is responsible for the glucuronidation. Should this study indicate involvement of UGTs in the drug metabolism, the recommended followup is to identify the metabolizing UGT(s) (see also the flowchart in the FDA new draft guidance).
The compound is incubated in test system, typically liver microsomes (different species available). Formation of glucoronides is detected by validated UPLC-MS/MS analytics.

2) UGT-Id – Pinpointing the specific UGT enzyme responsible for the glucuronidation of the compounds

This study is meant to identify the UGT enzyme(s) responsible for the glucuronidation and thus it is most often used as UGT-Pilot follow-up study. It is thus analogous to →our CYP identification assay (see this page for more). We currently have analytical assays for the 10 most common human UGT enzymes, including UGT1A1 (see also the FDA new draft guidance).
The compound is incubated with insect cell expressed human UGT enzymes (Supersomes). Formation of the gulucorinides is detected by UPLC-MS/MS analytics.

3) Inhib-UGT – Detection of the UGT inhibition by the studied compound(s)

This study is for detecting whether the compounds inhibit the activity of a specific UGT enzyme. This is analogous to →our CYP inhibition assay (see this page for more). We are detecting the potency to inhibit any of the 10 most common human UGTs.
The compound is incubated with a specific reporter substrate and insect cell expressed human UGT enzymes (Supersomes). The inhibition is detected by lower amounts of the glucuronidation on the reporter substrates, as detected by a specific UPL-MS/MS analytics.

It should be noted that a compound can inhibit the UGT enzyme activity, even though it would not be metabolized itself by the enzyme, and thus Inhib-UGT study is recommended to be doen irregardless of the results from the UGT-Pilot and UGT-Id studies.

Other phase II conjugation metabolism assays

These UGT specific assays will soon be followed with analytical assays for other classes of phase II metabolizing enzymes as well as various phase II enzyme induction assays.

Promotional offer for phase II conjugation metabolism studies

We offer a special 20% discount on phase II conjugation metabolism studies, which have been ordered during March-April, 2012. The promotional offer also includes 25% discount on CYP inhibition and CYP identification studies, when ordered together with phase II conjugation metabolism studies. This promotional offer will also include the other phase II conjugation metabolism assays that will be launched during this period.

Send PHASE II Promo offer

Please contact us for more information.