The pharmacokinetics of methimazole in pregnant patients after oral administration of carbimazole.

Skellern, G.G.; Knight, B.I.; Otter, M.; Low, CJ; Alexander, W. D.

doi:10.1111/j.1365-2125.1980.tb05824.x

Cited by 22 publications

(5 citation statements)

References 6 publications

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“…We are aware of only one previous article describing the effect of pregnancy on human FMO3‐related activity. In this work, the apparent clearance of methimazole was found to be higher (164 ml min −1 vs. 110 ml min −1 ) in pregnant hyperthyroid patients compared with nonpregnant patients after administration of 10 mg oral carbimazole, which is efficiently hydrolysed to methimazole [10]. Also of note is that hepatic FMO enzymes in rabbits and sheep are induced during pregnancy [11, 12].…”

Section: Effect Of Pregnancy On the Nicotine N′‐oxide Metabolic Ratiosmentioning

confidence: 99%

Effect of pregnancy on a measure of FMO3 activity

Hukkanen¹,

Dempsey²,

Jacob³

et al. 2005

Brit J Clinical Pharma

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Flavin-containing monooxygenases (FMO) are a family of microsomal enzymes that catalyse the oxygenation of xenobiotics [1]. Six FMO genes exist in humans, but only FMO3 enzyme is abundantly expressed in human liver. FMO3 contributes to the metabolism of several drugs including methimazole, nicotine, cimetidine, ranitidine, tamoxifen, and clozapine [1,2]. Dysfunctional FMO3 enzymes with deficient N-oxygenation of dietary trimethylamine cause trimethylaminuria (fish-odour syndrome).FMO3 is the main enzyme responsible for nicotine N ¢ -oxide formation, which is a minor pathway of nicotine metabolism. The FMO content of human liver microsomes is correlated with nicotine N ¢ -oxide formation, and N ¢ -oxygenase activity is abolished by FMO inhibitors in vitro [3]. Also, cDNA-expressed FMO3 is active in nicotine N ¢ -oxide formation [4]. A preliminary report on two siblings with fish-odour syndrome showed impaired urinary excretion of nicotine N ¢ -oxide compared with normal subjects [5]. Methimazole, an antithyroid agent and FMO3 inhibitor, has been reported to reduce nicotine N ¢ -oxide excretion [6]. Thus, formation of nicotine N ¢ -oxide can be used as a probe of human FMO3 activity [1].We recently published a study on pregnant smokers investigating the effect of pregnancy on nicotine and cotinine metabolism [7]. Ten subjects were given deuterium-labelled nicotine-d 2 and cotinine-d 4 infusion (30 or 45 m g/kg -1 of each compound) during pregnancy and postpartum. The systemic clearance was increased by 60% and 140% for nicotine and cotinine, respectively, in pregnancy compared with postpartum. This increase is most likely mediated by the induction of cytochrome P450 2A6, the main enzyme metabolizing nicotine and cotinine [8].Urine samples were collected and nicotine and metabolite concentrations were analysed by gas chromatography -mass spectrometry [7]. We have now reanalysed the data to examine the effects of pregnancy on the urinary ratio of nicotine N ¢ -oxide/nicotine, as an index of FMO3 activity. Ten subjects completed the study; a urine sample from one subject was lost. We measured both nicotine N ¢ -oxide-d 2 and nicotine-d 2 concentrations in urine samples collected over 8 h following the infusion in nine subjects during pregnancy and postpartum. In two subjects the calculation of the urine ratio during pregnancy was not possible because the concentration of nicotine (one subject) or concentration of nicotine N ¢ -oxide (one subject) was below the limit of quantification. In the remaining subjects the ratio of nicotine N ¢ -oxide/nicotine was substantially increased during pregnancy compared with postpartum (2.03 vs. 0.78; paired t-test, P = 0.017; 95% CI of the difference 0.5-2.0) ( Table 1).A possible confounding factor is that renal clearance of nicotine is pH-dependent, whereas nicotine N ¢ -oxide excretion is not. On average, pregnancy increases urine pH by 0.3-0.4 units [9] and might increase the nicotine N ¢ -oxide/nicotine ratio by decreasing nicotine excretion. Urine pH values were not recorded...

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Section: Effect Of Pregnancy On the Nicotine N′‐oxide Metabolic Ratiosmentioning

confidence: 99%

Effect of pregnancy on a measure of FMO3 activity

Hukkanen¹,

Dempsey²,

Jacob³

et al. 2005

Brit J Clinical Pharma

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“…Changes in pharmacokinetics have been seen with drugs other than anticonvulsants. , <, AMethimazole has been reported to have an apparent * A A clearance in pregnant hyperthyroid patients which is 65 , significantly greater than in non-pregnant women 0 2 4 6 8 (Skellern et al, 1980). The only report suggesting the Time (h) possibility of reduced clearance in pregnancy is the finding that caffeine has a longer half life in pregnant ,ure 3 Observed (0) and calculated (A) supine compared to non-pregnant controls (Knutti et istolic blood pressure in a representative subject~) rX = 0 80~~~~~a l .…”

Section: Resultsmentioning

confidence: 99%

Labetalol disposition and concentration‐effect relationships during pregnancy.

Pc¹,

Butters²,

Kelman³

et al. 1983

Brit J Clinical Pharma

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. 3 A linear model relating labetalol concentration to effect successfully described the antihypertensive action of labetalol in the pregnant patients. Supine systolic blood pressure fell by 0.38 (0.14-0.91) mm Hg per ng ml-' of labetalol and diastolic by 0.36 (0.21-1.14) mm Hg per ng ml-' of labetalol. In the other two groups labetalol did not lower pressure sufficiently to allow modelling to be performed. 4 We conclude that pregnancy does not alter the clearance or volume of distribution of labetalol. Modelling techniques can be applied successfully to drug induced blood pressure changes during pregnancy.

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“…In one study of pregnant patients with hyperthyroidism, the plasma half-life, plasma volume of distribution and clearance of propylthiouracil were no different from those of non-pregnant patients with hyperthyroidism [41] . Another study, however, showed that carbimazole clearance was greater in pregnant women with hyperthyroidism than in non-pregnant patients [42] . In a further report, the serum concentrations of propylthiouracil were lower in the third trimester of pregnancy than in the postpartum, although the dose range of propylthiouracil required in pregnancy was similar to that required in the non-pregnant state [43] .…”

Section: Antithyroid Drug Treatment In Pregnancymentioning

confidence: 96%