1. D0870, an azole antifungal agent, produced dose-related increases in total cytochrome P450 and aldrin epoxidase when administered as 14 daily oral doses (0, 0.5, 2.5 and 12.5 mg/kg/day) to the male rat. Administered as single doses, D0870 increased pentobarbitone-sleeping time in a dose-related manner. 2. In human hepatic microsomal incubations, D0870 produced pronounced inhibition of CYP2C9 (tolbutamide hydroxylase) and, to a lesser degree, CYP3A4 (testosterone 6beta-hydroxylase), but had more limited effects on CYP1A2, 2C19 and 2D6 activity. In comparison with ketoconazole, itraconazole and fluconazole, D0870 was the most potent inhibitor of CYP2C9 activity. It is predicted that D0870 may inhibit the in vivo clearance of CYP2C9 substrates by approximately 58%, thereby increasing their steady-state concentrations by 2.4 times, which would be of clinical significance for some compounds. 3. During incubation of [14C]-D0870 with cultured human hepatocytes for up to 72 h, two discrete metabolites (A and B) were formed. Formation of metabolite A was abolished by both quinidine and ketoconazole and is probably CYP3A4-mediated, whereas generation of metabolite B did not appear to be dependent on cytochrome P450. 4. D0870 has potential to produce both induction and inhibition of cytochrome P450 enzymes in man.

British Journal of Clinical PharmacologyVolume 43, Issue 1 p. 1-2 Free Access New cover—renewed commitment David J. Back, David J. BackSearch for more papers by this authorGordon T. Mclnnes, Gordon T. MclnnesSearch for more papers by this authorGeoff T. Tucker, Geoff T. TuckerSearch for more papers by this author David J. Back, David J. BackSearch for more papers by this authorGordon T. Mclnnes, Gordon T. MclnnesSearch for more papers by this authorGeoff T. Tucker, Geoff T. TuckerSearch for more papers by this author First published: 18 July 2008 https://doi.org/10.1111/j.1365-2125.1997.tb00128.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Lock SP. Structured abstracts. Br Med J 1988; 297: 156. 2 Lock SP. How editors survive. Br Med J 1976; 3: 1118– 1119. 3 Hartley J, Sydes M. Structured abstracts in the social sciences: presentation, readability, search and recall. European Science Editing 1995; 56: 6– 7. 4 Hill AB. The reasons for writing. Br Med J 1965; 2: 626– 627. Volume43, Issue1January 1997Pages 1-2 ReferencesRelatedInformation

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine (Lamisil), have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol and cyclosporin by human liver microsomes (n = 4) in vitro. Ketoconazole caused marked inhibition of all enzyme activities with mean IC50 values (concentration producing 50% inhibition) of 17.9 μM (tolbutamide hydroxylase), 1.9 μM (ethinyloestradiol 2–hydroxylase), 2.0 μM (cyclosporine N-demethylase) and 2.1 μM (cyclosporine hydroxylase). At 50 μM terbinafine concentration, inhibition was less than 5% for tolbutamide, approximately 12% for both cyclosporin pathways and 30% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P-450 isozymes as ketoconazole.

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.

The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostoray following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 ± 10.9% (± S.D.) compared to a control value of 45.0 ± 6.1% (p > 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 ± 13.1% compared to 104.6 ± 22.3% in the controls (p 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.

The effects of the quinoline derivatives amodiaquine (AQ), chloroquine (CQ), mefloquine (MQ), primaquine (PQ), quinine (Q) and quinidine (QD) on in vitro hepatic metabolism has been studied using as substrates ethinyloestradiol (EE2) and tolbutamide (TOL). The 2-hydroxylation of EE2 and the hydroxylation of TOL were determined in the presence of variable concentrations of each compound. MQ, PQ, AQ and Q significantly inhibited EE2 metabolism at each of the concentrations studied (0.1, 0.2 and 0.5 mM) as shown by an increase in the percentage of unmetabolised EE2. QD significantly inhibited metabolism at 0.2 and 0.5 mM but CQ was without effect. In terms of recovery of 2-OHEE2, PQ was the most potent inhibitor. At an inhibitor concentration of 0.5 mM the order of potency was PQ greater than or equal to MQ greater than or equal to Q greater than or equal to QD greater than or equal to AQ greater than or equal to CQ. TOL hydroxylase activity in control microsomes was 1.52 +/- 0.33 nmol. min-1 X mg protein-1. The order of potency of the inhibitors (0.5 mM) was PQ greater than or equal to MQ greater than or equal to Q greater than or equal to QD greater than or equal to AQ greater than or equal to CQ. These data provide further evidence of the inhibitory potential of some of the quinoline derivatives. PQ, MQ, and to a lesser extent Q produce the most marked inhibitory effects. QD and AQ are of intermediate potency and CQ is essentially non-inhibitory.

The effect of the new antimalarial drug mefloquine (MQ) on hepatic drug metabolism in the rat has been studied in vitro and in vivo using three different substrates, aminopyrine, ethinyloestradiol and tolbutamide. Comparative studies have been performed with primaquine (PQ). In vitro, both MQ and PQ inhibited aminopyrine N-demethylase activity and the concentration required to produce 50% inhibition was 0.2 mM for MQ and approximately 0.1 mM for PQ. Lineweaver-Burk plots indicated inhibition by both antimalarials to be non-competitive. Both MQ and PQ produced comparable inhibition of ethinyloestradiol metabolism in vitro with the percentage recovery of the major metabolite, 2-hydroxyethinyloestradiol being reduced from 49.3 +/- 10.8 to 5.1 +/- 3.1 (0.5 mM MQ) and 1.5 +/- 0.4% (0.5 mM PQ, mean +/- S.D.). Following acute administration of MQ and PQ to rats (25 mg kg-1) recovery of hydroxytolbutamide the major metabolite of tolbutamide, was reduced. In the period 0-8 hr, MQ caused a reduction in recovery from 54.4 +/- 3.1 to 9.3 +/- 3.4% and PQ from the control level to 32.2 +/- 14.1%. There is therefore clear evidence that MQ inhibits hepatic microsomal enzymes both in vitro and in vivo. The more pronounced effect of MQ in vivo, in comparison with PQ, is probably a reflection of differences in the kinetics of the two antimalarials. The range of substrates studied indicate a non-selective and widespread inhibitory effect of these drugs on oxidative enzymes.

A number of major studies in the past 4 years have facilitated assessment of drug interactions with the steroids in oral contraceptive (OCs). In 8 women receiving a single dose of Minovlar during rifampicin therapy and another dose 1 month after stopping rifampicin, rifampicin reduced the half-life of norethisterone from 6.2 to 3.2 hours, the half-life of ethinyl estradiol (EE) from 6.5 to 2.9 hours, and considerably reduced the bioavailability of both. All patients showed evidence of microsomal enzyme induction. Because of the wide variation in response, women using rifampicin should not use OCs, especially low-dose OCs. A recent study described the effects of the anticonvulsant phenobarbitone (30 mg twice daily) on 4 women taking OCs who were studied 1 month before and 2 months after phenobarbitone was started. 2 women with significant falls in plasma EE concentration developed breakthrough bleeding while the other 2 showed no change in EE or norgestrel. Sex-hormone-blinding globulin capacity increased by 28% during therapy, reducing the free concentration of progestagen in plasma. Most practitioners advise the use of other contraceptive methods with anticonvulsants. Although there is no doubt that in experimental animals antibiotics interfere with the enterohepatic circulation of synthetic steroids, clinical studies have failed to show any systematic interaction between ampicillin and OC steroids in humans, and more recent studies have failed to show interaction between either erythromycin or tetracycline and OCs in women with acne vulgaris or cotrimoxazole and OCs in normal volunteers. Further data are needed before clear advice can be given to women. Ascorbic acid has recently been found to enhance the effect of OCs: the plasma concentration of EE is significantly higher in OC users taking 1 g of ascorbic acid than in the same subjects taking the OC alone.

Conference Article| October 01 1975 The Distribution of Lysergic Acid Diethylamide ([3H]LSD) in the Rat JAGMOHAR K. G. SINGH; JAGMOHAR K. G. SINGH 1Department of Pharmacology and Therapeutics, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, U.K. Search for other works by this author on: This Site PubMed Google Scholar DAVID J. BACK DAVID J. BACK 1Department of Pharmacology and Therapeutics, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1975) 3 (5): 688. https://doi.org/10.1042/bst0030688a Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation JAGMOHAR K. G. SINGH, DAVID J. BACK; The Distribution of Lysergic Acid Diethylamide ([3H]LSD) in the Rat. Biochem Soc Trans 1 October 1975; 3 (5): 688. doi: https://doi.org/10.1042/bst0030688a Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1975 Biochemical Society1975 Article PDF first page preview Close Modal You do not currently have access to this content.