Oral contraceptive steroid plasma concentrations in smokers and non-smokers.

Crawford, Francesca E.; Back, D J; Orme, M.; Breckenridge, A

doi:10.1136/bmj.282.6279.1829

Cited by 21 publications

(4 citation statements)

References 2 publications

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“…Smoking may also affect production of ovarian steroids by altering steroid-producing enzymes. [24][25][26] MacMahon and colleagues 27 showed that urinary estrogens are reduced in smoking women during the luteal but not during the follicular phase ( Fig. 5), consistent with the theory that ovarian production and/or urinary excretion of estrogen is impaired by smoking.…”

Section: Smoking and Conception Epidemiologysupporting

confidence: 58%

The Effect of Smoking on Oogenesis, Fertilization, and Implantation

Mattison¹,

Plowchalk²,

Meadows³

et al. 1989

Semin Reprod Med

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Section: Smoking and Conception Epidemiologysupporting

confidence: 58%

The Effect of Smoking on Oogenesis, Fertilization, and Implantation

Mattison¹,

Plowchalk²,

Meadows³

et al. 1989

Semin Reprod Med

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“…Thus evidence is accumulating that smoking induces enzymes in the P450IA gene family which are at least partially responsible for the metabolism of 7-ethoxyresorufin, theophylline and oestradiol. Smoking does not affect the disposition of 17a-ethinyloestradiol [26,27].…”

mentioning

confidence: 89%

Differences in the cytochrome P-450 isoenzymes involved in the 2-hydroxylation of oestradiol and 17 α-ethinyloestradiol. Relative activities of rat and human liver enzymes

Ball¹,

Forrester

Wolf

et al. 1990

Biochemical Journal

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The metabolism of oestradiol and 17 alpha-ethinyloestradiol to their 2-hydroxy derivatives is an important determinant in their biological effects. In this work, we have investigated which rat or human cytochrome P-450 isoenzymes are involved in catalysing these reactions. Oestradiol 2-hydroxylation was catalysed by a wide variety of rat cytochrome P-450s from gene families P450IA, P450IIB, P450IIC and P450IIIA. Interestingly, 17 alpha-ethinyloestradiol, which only differs structurally from oestradiol at a position distant from the site of oxidation, was metabolized predominantly by members of the P450IIC gene subfamily. In order to establish which enzymes are responsible for the oxidation of these substrates in man, antibodies to rat liver cytochrome P-450 isoenzymes were used to inhibit these reactions in a panel of human liver microsomal fractions. Also, possible correlations between the proteins recognized by the antibodies and the 2-hydroxylation rate were determined. These experiments provide evidence that 2-hydroxylation of 17 alpha-ethinyloestradiol in man is catalysed by cytochromes from the P450IIC, P450IIE and P450IIIA gene families. In contrast, the major proteins involved in oestradiol metabolism are from the P450IA gene family, although members of the P450IIC and P450IIE gene families may also play a role. These data demonstrate that the differences in the capacity of rat P-450s to metabolize these substrates are also present in the comparable enzymes involved in man, and that a variety of factors will determine the rate of disposition of these compounds in man.

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“…This work was consequently extended to the clinical setting when the role of pathophysiological factors influencing drug kinetics was studied [8].At the same time that all the new drugs were introduced into clinical medicine, it was realized that coadministration of two or more drugs could result either in an increased or a diminished drug action, a phenomenon termed drug interaction. It was soon realized that changes in drug metabolism were a major mechanism due to either inhibition or induction of drugmetabolizing enzymes [4,10]. Particularly in the case of the oral anticoagulant warfarin, these metabolic interactions had detrimental consequences for the patients.…”

mentioning

confidence: 99%

“…Again Alasdair Breckenridge was active in the field right from the beginning, studying the contribution of gut wall to the presystemic metabolism of ethinyloestradiol and norethindrone. In these studies he and his coworkers showed that there was substantial conjugation by the gut wall of these drugs and outlined that this accounted for the rather low oral bioavailability of this class of compounds [2,3,10].…”

mentioning

confidence: 99%

Progress in clinical pharmacology over the last 20 years

Eichelbaum

2003

Brit J Clinical Pharma

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The late 1950s and early 1960s witnessed a dramatic change in the practice of medicine. At this time many drugs were introduced into the clinic which for the first time allowed the effective treatment of many common diseases such as hypertension, angina pectoris, depression, schizophrenia, carcinomas and leukaemias to name only a few. Right from the beginning of modern drug therapy, it was observed that there was substantial variability among patients both in therapeutic efficacy and the occurrence of side-effects. The realization that dose was a poor predictor of therapeutic response raised the curiosity of clinicians and pharmacologists in elucidating the mechanisms responsible. This was the starting point for the development of clinical pharmacology. Of great importance for clinical pharmacology was the work carried out by the groups of R. T. Williams at St Mary's Hospital and B. B. Brodie in the Laboratory of Chemical Pharmacology at the NIH who pioneered the work on drug metabolism. The discovery of drug-metabolizing enzymes and realizing that their activity determined the rate at which drugs were eliminated from the body was instrumental for our understanding of why patients respond differently to the same dose of a drug. In a number of elegant studies, B. B. Brodie and coworkers showed that species differences in the duration of hexobarbitone action after administration of the same dose were not due to differences in sensitivity but a consequence of pronounced species differences in the rate of biotransformation of hexobarbitone. Moreover, he showed that the blood concentration at the time of awakening was very similar among the various species and in man. It is still worth reading his famous Toral Sollmann Award lecture Of Mice, Microsomes and Man at the ASPET Meeting (August 13, 1963). In this lecture, many principles that can account for variability in drug response between animals and humans were put forward. The concept that drug effects are not related to the dose administered but rather the plasma concentration achieved, and that in analogy to species differences, patient-to-patient variability in response can be explained by different plasma concentrations, was instrumental for clinical pharmacology.Rather than giving a detailed account on the progress being made, I would like to focus on Alasdair Breckenridge's contribution to the field of drug metabolism. It is in the area of drug metabolism and especially in understanding the various factors that could affect the activity of drug-metabolizing enzymes where Alasdair Breckenridge has made substantial contributions to clinical pharmacology throughout his professional career. His interest was not restricted to the experimental findings but to explore the consequences of his results for drug action and side-effects in patients. It is a persistent feature of his work that observation of a clinical problem led him to carry out experimental work to understand the mechanisms responsible and then to test the hypothesis generated in his laboratory experi...

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Oral contraceptive steroid plasma concentrations in smokers and non-smokers.

Abstract: Esterase activity in leukocytes demonstrated by the use of naphthol AS-D chloroacetate substrate.

Cited by 21 publications

References 2 publications

The Effect of Smoking on Oogenesis, Fertilization, and Implantation

The Effect of Smoking on Oogenesis, Fertilization, and Implantation

Differences in the cytochrome P-450 isoenzymes involved in the 2-hydroxylation of oestradiol and 17 α-ethinyloestradiol. Relative activities of rat and human liver enzymes

Progress in clinical pharmacology over the last 20 years

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