Drug Disposition Overview - Pharmacology and at UCSD
Drug Disposition Overview - Pharmacology and at UCSD
Drug Disposition Overview - Pharmacology and at UCSD
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BIOM/PHAR 255 Winter 2013 Halpert - Jan. 17, 2013<br />
Properties of UGTs<br />
• Normally detoxifying, but can be involved in bioactiv<strong>at</strong>ion<br />
• Glucuronides excreted in bile or urine<br />
– Smaller glucuronides excreted in urine<br />
– Larger glucuronides excreted in bile (undergo enterohep<strong>at</strong>ic<br />
circul<strong>at</strong>ion)<br />
• Genetic defect in UGT1A1 leads to hyperbilirubinemia<br />
diseases<br />
• Glucuronid<strong>at</strong>ion can be impaired when cofactor is<br />
depleted (e.g fasting)<br />
18 of 22<br />
OH<br />
OCH 2 CHCH 2 NHCH(CH 3 ) 2<br />
Propanolol<br />
(Alkylhydroxy-glucuronide)<br />
N<br />
CH 2 CH 2 CH 2 N<br />
Imipramine<br />
(Qu<strong>at</strong>ernary-glucuronide)<br />
Examples: UGT Substr<strong>at</strong>es<br />
(CH 3 ) 2<br />
HO<br />
O<br />
Morphine<br />
OH<br />
H 2 N<br />
N<br />
N<br />
CH3 N-Hydroxy-PhIP<br />
(N-glucuronide)<br />
N<br />
Benzidine<br />
(Arylamine-glucuronide)<br />
A single gene encodes multiple UGTs with differing<br />
substr<strong>at</strong>e preferences<br />
(Ritter et al, 1992)<br />
Each isoform of UGT1 results from differential splicing of<br />
exon1s (N-terminal 287 AA) to common exons 2-5 (245 AA).<br />
1A12<br />
1A10 1A8 1A6 1A4 1A2 2 3 4 5<br />
1A11 1A9 1A7 1A5 1A3 1A1<br />
pseudogene<br />
H<br />
OH<br />
NH 2<br />
UGT1A
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