We tested a health education intervention program to reduce passive smoking in infancy. The aim was to develop an instrument for study of tobacco smoke exposure and childhood respiratory illness. One hundred and eighty-four women who had smoked during pregnancy were allocated by month of delivery to an intervention group, to a minimal contact group, or to a follow-up only comparison group. Exposure to smoke was assessed 3 months later by questionnaire and by measurement of cotinine in samples of maternal and infant urine. There was a reduction in maternal smoking associated with contact with research staff, but this was not statistically significant. There were no differences between the groups in the exposure of infants to tobacco smoke. Reasons for this finding may include the timing of the intervention, the heterogeneity of the target group, and the manner in which information was presented on health risks caused by parental smoking.
Salicylic acid and acetylsalicylic acid (aspirin) disposition after an oral dose of aspirin, 900 mg (equivalent to 689.7 mg of salicylic acid) was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Salicylic acid clearance was 61% higher in males compared to the control female group, an effect due largely to enhanced activity of the glycine conjugation pathway (salicyluric acid formation) in males. Salicylic acid clearance was 41% higher in OCS‐users compared to the control female group due to increases in both the glycine and glucuronic acid conjugation pathways in the pill users. There was no difference in any salicylic acid disposition parameter between males and OCS‐users. Area under the plasma concentration‐time curve (AUC) and elimination half‐life of aspirin was significantly greater and aspirin plasma hydrolysis rate was significantly lower in both female groups compared to males. There was no difference between OCS‐users and the control female group in any of these parameters. Aspirin AUC and elimination half‐life were significantly correlated with aspirin plasma hydrolysis rate. These data confirm the importance of hormonal factors in the regulation of drug conjugation reactions in humans and suggest that sex‐related differences in salicylic acid and aspirin disposition may be of clinical importance.
SUMMARY The determinants of urine cotinine levels were studied in a group of 101 infants aged 3 months, including 79 infants whose mothers were current smokers. At a pre-arranged home visit the infants' mothers completed an interviewer-administered questionnaire, and samples of maternal urine and breast milk and infants' urine were collected. Cotinine and nicotine levels were determined by gas-liquid chromatography. Infant urine cotinine levels ranged from 0 to 140 1ig/l (0-1120 ng cotinine/mg creatinine). A linear dose response relation between mother's smoking rate and infant urine cotinine level was observed among breast-fed infants (r= 079, p < 0-001). The relation was weaker among infants fed by both breast and bottle (r = 0 56, p=0.01) and was not apparent among bottle-fed infants (r = 0 15, p = 0 16). In addition to mode of feeding and mother's smoking rate, mother's smoking "hygiene" (assessed by the reported frequency of smoking while feeding and with infant in same room) was independently associated with infant urine cotinine level. Father's smoking pattern and exposure to smoke outside the household did not relate significantly to infant cotinine levels. We conclude that when mothers smoke, breast feeding is the principal determinant ofcotinine in infants' urine. It is likely that most ofthis cotinine comes from cotinine in mothers' breast milk, but further research is needed to establish how much nicotine is ingested by breast-fed infants of mothers who smoke, and to investigate possible health effects.There is growing evidence of health risks due to passive smoking, especially in infancy and early childhood.' 2 Accurate biochemical measures of passive smoking are needed to identify these risks precisely, and to quantify the benefits of any antismoking intervention. Previous work has shown that cotinine, a major metabolite of nicotine, can be measured in blood, saliva, and urine and is a better indicator ofexposure to tobacco smoke than is carbon monoxide, nicotine or thiocyanate.3 I However, more information is required before cotinine can be used as a quantitative guide to exposure.A number of factors are likely to influence cotinine levels in urine. One study has already shown a dose response relation between amount smoked by parents and levels of cotinine in urine and saliva of infants.5
AimsThe aims of this study were to examine the in vitro enzyme kinetics and CYP isoform selectivity of perhexiline monohydroxylation using human liver microsomes. Methods Conversion of rac-perhexiline to monohydroxyperhexiline by human liver microsomes was assessed using a high-performance liquid chromatography assay with precolumn derivatization to measure the formation rate of the product. Isoform selective inhibitors were used to define the CYP isoform profile of perhexiline monohydroxylation. Results The rate of perhexiline monohydroxylation with microsomes from 20 livers varied 50-fold. The activity in 18 phenotypic perhexiline extensive metabolizer (PEM) livers varied about five-fold. The apparent K m was 3.3 ± 1.5 µ M , the V max was 9.1 ± 3.1 pmol min − 1 mg − 1 microsomal protein and the in vitro intrinsic clearance (V max /K m ) was 2.9 ± 0.5 m l min − 1 mg − 1 microsomal protein in the extensive metabolizer livers. The corresponding values in the poor metabolizer livers were: apparent K m 124 ± 141 µ M ; V max 1.4 ± 0.6 pmol min − 1 mg − 1 microsomal protein; and intrinsic clearance 0.026 µ l min − 1 mg − 1 microsomal protein. Quinidine almost completely inhibited perhexiline monohydroxylation activity, but inhibitors selective for other CYP isoforms had little effect. Conclusions Perhexiline monohydroxylation is almost exclusively catalysed by CYP2D6 with activities being about 100-fold lower in CYP2D6 poor metabolizers than in extensive metabolizers. The in vitro data predict the in vivo saturable metabolism and pharmacogenetics of perhexiline.
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