An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity.

Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p < 0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p < 0.001) compared with rat liver microsomes. MPA UGT activities were reduced >80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.     

Primary ovarian pregnancy two years after bilateral tubal ligation. A case report

This is the first documented case of intrafollicular ovarian pregnancy following bilateral tubal ligation. The patency of the previously ligated tube was demonstrated by hysterosalpinography. It appears that the incidence of ovarian pregnancy is not related to the rising incidence of tubal pregnancy.     

Effect of airway resistance on perceived odor intensity

Because of the wide range of human nasal anatomic configurations, some people sniff odorants against comparatively high resistances. To assess the relationship between sniff resistance and olfaction, ten subjects without nasal pathology or complaint were asked to estimate the perceived magnitude of the odorant, ethyl butyrate, at each of four concentrations and against each of four different resistances. In addition, the airflow profile of the subjects' sniffs was monitored during the performance of the odor task. As expected, perceived intensity increased with concentration, but more noteworthy was the finding that perceived intensity decreased with increasing resistance. Initially, this latter finding, together with the lack of interaction between concentration and resistance, suggested an olfactory analogue to conductive hearing losses. However, the sniffing data suggested that under the conditions of the experiment, the subjects attempted to maintain consistent sniffing behavior across the 16 different treatment combinations of concentration and resistance. These observations, taken together with the finding that subjects could estimate the perceived effort of sniffing, give support to the concept of a perceptual constancy model in olfaction. That is, olfactory magnitude may depend not only on the odorant itself, but also on the perceived effort associated with the sniff.     

Zur Komplementbindung bei Gonorrhöe

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Einzelreferate und Buchbesprechungen

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Einzelreferate und Buchbesprechungen

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Einzelreferate und Buchbesprechungen

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Beitrag zur Entstehung der Luetischen Reagine in den Lumbalflüssigkeiten

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