Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance.

AIM: To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT ). METHODS: Microsomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CLint,u,UGT ) for PRO and morphine (MOR; 3- and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and MOR. RESULTS: MPPGK was 9.3 ± 2.0 mg g(-1) (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg(-1) ) was 2.7 fold higher than that reported for HLM. CONCLUSIONS: Scaled renal PRO glucuronidation CLint,u,UGT was double that of liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates

Marked Reduction in Obstructive Sleep Apnea Severity in Slow Wave Sleep

Introduction: Obstructive sleep apnea (OSA) is widely accepted to improve during slow wave sleep (SWS) compared to lighter stages of NREM sleep. However, supporting data to establish the magnitude and prevalence of this effect is lacking. Consequently, we examined this phenomenon, controlling for posture, in a large group of patients investigated for OSA at an academic clinical sleep service. Methods: A detailed retrospective analysis was conducted on data obtained from each 30-sec epoch of sleep in 253 consecutive full-night diagnostic polysomnography studies performed over a 3-month period. Respiratory and arousal event rates were calculated within each stage of sleep, in the supine and lateral postures, and across the whole night, with OSA patients classified on the basis of an overall apnea-hypopnea index (AHI) ≥ 15 events/h. Central sleep apnea (CSA) patients were defined by a central apnea index ≥ 5/h. Sleep latency and time, and respiratory and arousal event rates in OSA, CSA, and non-OSA patients were compared between sleep stages and postures using linear mixed model analysis. The numbers of patients achieving reduced event rates in SWS and in the lateral posture were also examined. Results: There were 171 patients with OSA, 14 with CSA, and 68 non-OSA patients. OSA patients took significantly longer to achieve slow wave and REM sleep (p < 0.001) than non-OSA patients and had less stage 4 sleep (p = 0.037). There were striking improvements in AHI and arousal index (AI) from stage 1 to 4 NREM sleep (p < 0.001), with intermediate levels in REM sleep. AHI and AI were also markedly reduced in lateral versus supine sleep in all sleep stages (p < 0.001), with an effect size comparable to that of the slow wave sleep effect. The majority of OSA patients achieved low respiratory event rates in SWS. Eighty-two percent of patients achieved an AHI < 15 and 57% < 5 events/hour during stage 4 sleep.Rajeev Ratnavadivel, Nuy Chau, Daniel Stadler, Aeneas Yeo, R. Doug McEvoy, Peter G. Catchesid