Differentiation of BIRADS-4 small breast lesions via Multimodal Ultrasound Tomography.

PURPOSE: To demonstrate the use of a new 3D diagnostic imaging technology, termed Multimodal Ultrasonic Tomography (MUT), for the detection of solid breast lesions < 15 mm in maximum dimension. METHODS AND MATERIALS: 3D MUT imaging was performed on 71 volunteers presenting BIRADS-4 nodules, asymmetrical densities, and architectural distortions in X-ray mammograms, who subsequently underwent biopsy. MUT involved D tomographic imaging of the pendulant breast in a water bath using transmission ultrasound and constructed multimodal images corresponding to refractivity and frequency-dependent attenuation (calibrated relative to water). The multimodal images were fused into composite images and a composite index (CI) was calculated and used for diagnostic purposes. The composite images were evaluated against results of histopathology on biopsy specimens. RESULTS: Histopathology revealed 22 malignant and 49 benign lesions. The pixels of 22 malignant lesions exhibited high values in both refractivity and attenuation, resulting in CI values > 1. In contrast, 99.9% of benign lesions and normal tissue pixels exhibited lower values of at least one of the attributes measured, corresponding to CI values < 1. CONCLUSIONS: MUT imaging appears to differentiate small malignant solid breast lesions as exhibiting CI values >1, while benign lesions or normal breast tissues exhibit CI values <1. KEY POINTS: • MUT was able to detect all 22 biopsy-confirmed malignant lesions. • MUT was able to differentiate the malignant from the benign lesions. • Additional MUT detections outside the biopsy area must be evaluated prospectively.

Novel technology of multimodal ultrasound tomography detects breast lesions.

OBJECTIVES: To introduce a new three-dimensional (3D) diagnostic imaging technology, termed "multimodal ultrasonic tomography" (MUT), for the detection of breast cancer without ionising radiation or compression. METHODS: MUT performs 3D tomography of the pendulant breast in a water-bath using transmission ultrasound in a fixed-coordinate system. Specialised electronic hardware and signal processing algorithms are used to construct multimodal images for each coronal slice, corresponding to measurements of refractivity and frequency-dependent attenuation and dispersion. In-plane pixel size is 0.25 mm × 0.25 mm and the inter-slice interval can vary from 1 to 4 mm, depending on clinical requirements. MUT imaging was performed on 25 patients ("off-label" use for research purposes only), presenting lesions with sizes >10 mm. Histopathology of biopsy samples, obtained from all patients, were used to evaluate the MUT outcomes. RESULTS: All lesions (21 malignant and four benign) were clearly identified on the MUT images and correctly classified into benign and malignant based on their respective multimodal information. Malignant lesions generally exhibited higher values of refractivity and frequency-dependent attenuation and dispersion. CONCLUSION: Initial clinical results confirmed the ability of MUT to detect and differentiate all suspicious lesions with sizes >10 mm discernible in mammograms of 25 female patients.

Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone.

An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin. These observations suggested that interactions between warfarin and other drugs might be manifest stereo-specifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.

GABAC receptor sensitivity is modulated by interaction with MAP1B.

GABA(C) receptors contain rho subunits and mediate feedback inhibition from retinal amacrine cells to bipolar cells. We previously identified the cytoskeletal protein MAP1B as a rho1 subunit anchoring protein. Here, we analyze the structural basis and functional significance of the MAP1B-rho1 interaction. Twelve amino acids at the C terminus of the large intracellular loop of rho1 (and also rho2) are sufficient for interaction with MAP1B. Disruption of the MAP1B-rho interaction in bipolar cells in retinal slices decreased the EC(50) of their GABA(C) receptors, doubling the receptors' current at low GABA concentrations without affecting their maximum current at high concentrations. Thus, anchoring to the cytoskeleton lowers the sensitivity of GABA(C) receptors and provides a likely site for functional modulation of GABA(C) receptor-mediated inhibition.

The teaching of clinical pharmacology in Europe and North America.

A recent survey conducted under the auspices of the WHO shows that on average in European medical schools only 28 hours of teaching are devoted to clinical pharmacology, whereas over 100 hours are devoted to pharmacology. In many schools no clinical pharmacology is taught, and there is a lack of trained individuals and posts in clinical pharmacology. In North America there is a similar lack of clinical pharmacology teaching.

Interactions between oral contraceptives and other drugs.

PIP: There is increasing evidence from various types of studies that commonly prescribed drugs can interact with OCs (oral contraceptives), leading to a decreased contraceptive efficacy. Additionally, contraceptive steroids influence the response to the other drug therapies as well. Antituberculous drugs enhance metabolism of the estrogenic component of OCs, thus reducing the contraceptive effect. Other types of drugs which have been shown to interfere with the contraceptive effect of OCs are: anticonvulsant, antibiotic, and analgesic drugs. The effect of OCs on anticoagulant, antihypertensive, antidiabetic, and antidepressant drugs is also outlined. Tables and graphs illustrate some of these disadvantegeous drug interactions.^ieng

Pharmacokinetics of indomethacin.

Plasma concentrations of indomethacin have been studied in 5 healthy volunteers after single and multiple doses (25 mg intravenously [iv], 25, 50, and 100 mg orally, 100 mg rectally, and 25 mg three times daily [tid]. In 8 other normal subjects and in 5 patients a 50-mg oral dose of indomethacin was given and the indomethacin concentration was followed from 8 to 32 hr after dosing. All analyses were carried out using a new mass fragmentographic method. After oral and rectal doses the plasma decay of indomethacin was biphasic, and the data were interpreted according to a 2-compartment open model. The half-life of the beta-phase varied between 2.6 and 11.2 hr. The volume of distribution ranged from 0.34 to 1.57 L/kg and the plasma clearance from 0.044 to 0.109 L/kg/hr. There was no evidence of dose-dependent elimination. Indomethacin was rapidly and well absorbed after oral dosing with peak plasma concentrations within 2 hr. Comparison with the area under the curve (AUC) after iv dosing indicated complete bioavailability. The AUC after rectal dosing indicated complete bioavailability, but the rate of absorption was slower than after oral administration. Indomethacin, 25 mg three times daily, was also given for 9 days to the same normal subjects; equilibrium concentrations obtained did not differ significantly (p greater than 0.1) from those predicted from single-dose data in the 5 subjects.

The interaction between indomethacin and probenecid. A clinical and pharmacokinetic study.

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas-liquid chromatographic method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3-wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 +/- 213 hr ng/ml to 4,181 +/- 384 hr ng/ml when probenecid was given, but there was no change in the plasma half-life of indomethacin. There was a reduction in the mean plasma clearance of indomethacin from 174 +/- 21 ml/kg/hr to 107 +/- 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distribution from 0,927 +/- 0.16 L/kg to 0.613 +/- 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacin from 8,967 +/- 867 microgram/day to 4,760 +/- 674 microgram/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 +/- 48 ml/min to 126 +/- 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.

Diethylcarbamazine disposition in patients with onchocerciasis.

Diethylcarbamazine (DEC), 0.5 mg/kg, was taken orally by six patients being treated for onchocerciasis. Blood samples were taken at timed intervals for 48 hr and urine and feces collected for 4 days. Plasma and urinary concentrations of DEC and DEC N-oxide were measured by gas-liquid chromatography. DEC appeared to be rapidly absorbed, with a peak plasma concentration of 150 to 250 ng/ml reached in 2 to 3 hr. There was a secondary rise in plasma DEC concentration at 5 to 6 hr in all patients. In contrast to the way the drug is eliminated in rats, in man it was by both renal and extrarenal routes, with small amounts (+/- 10%) being excreted as an N-oxide metabolite. DEC kinetics were also investigated in five normal subjects and the result were much the same. Clinical implications are discussed.

Propranolol in the control of blood pressure: a dose-response study.

In a double-blind crossover study, it has been shown that the hypotensive response to propranolol in 24 patients with essential hypertension was no greater at doses of 80, 160, or 240 mg twice daily than at 40 mg twice daily. A relationship was observed between dose and response as defined by the ability to achieve a standing diastolic blood pressure of 95 mm Hg. Four patients with low plasma renin activity (PRA) had no fall in blood pressure even at highest dose levels. Plasma propranolol levels in the groups were related to dose, and up to a concentration of 300 ng/ml, with degree of beta-adrenoceptor blockade; there was, however, no correlation with hypotensive response.

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension.

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagoinst of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metroprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 +/- 3.8 (SEM)/10 +/- 2.1 mm Hg in the lying position and 23 +/- 4.4/9 +/- 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady-state plasma concentrations of metoprolol varied 17-fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p less than 0.05) and decrease in exercise tachycardia (r = 0.65, p less than 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mg/kg. Metoprolol decreased PRA by 67 +/- 1.9 and 71 +/- 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p less than 0.05) but not to the plasma steady-state levels of metoprolol, the degree of beta receptor blockade, and the decrease in PRA.

Pharmacokinetic drug interactions with oral contraceptives.

Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used. Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aLuminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids. These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: The pharmacokinetics and clinical significance of the major drug interactions seen with oral contraceptives are reviewed, both drugs interfering with pill efficacy, and situations where pills interfere with action of other drugs. Drugs affecting contraceptive efficacy include anticonvulsants, antibiotics, rifampicin, griseofulvin, ascorbic acid, and acetaminophen. Phenytoin is the most common anticonvulsant reported to cause contraceptive failure. It as been established by measurements of steady-state ethinyl estradiol levels, sex hormone binding globulin levels, and pharmacokinetic drug concentration curves that both ethinyl estradiol and levonorgestrel levels are decreased during phenytoin and carbamazepine intake. Induction of certain cytochrome P450 isozymes is probably responsible. Neither the causation or even the existence of drug interaction with antibiotics is definitely known, although case reports of pregnancies abound. Rifampicin is an exception, where enzyme induction clearly occurs. Ascorbic acid and acetaminophen are atypical for increasing the therapeutic effect of ethinyl estradiol. The effect of benzodiazepines depends on the type of drug metabolism: drugs oxidized and nitroreduced, e.g. chlordiazepoxide, alprazolam, diazepam, and nitrazepam, exhibit reduced clearance during pill intake. Clearance of cyclosporin, prednisolone, alcohol, caffeine and theophylline are also slowed by orals. Pills accelerate clearance of salicylic acid and morphine.

Immediate decrease by hydrocortisone of the plasma half-life of antipyrine.

Infusion of hydrocortisone in man caused an immediate shortening of the plasma half-life of antipyrine. There was no change in the 'apparent' volume of distribution of antipyrine and the plasma concentrations of hydrocortisone during the infusion remained within physiological limits. Similar changes in plasma half-lives of antipyrine were observed in the dog, but in vitro studies of drug oxidation with dog liver failed to show any difference between biopsy samples taken before and during steroid infusion.Many drugs and chemicals are known to stimulate rates of drug oxidation in both man and animals. Administration of these inducing agents results in an increase in the activity of enzymes catalyzing drug oxidation, most of which are located with-in the endoplasmic reticulum of liver cells. In man there is usually a delay of 4-8 days before an appreciable change in rates of drug metabolism is seen when such an agent is administered (Breckenridge, Orme, Thorgeirsson, Davies & Brooks, 1971); in rats, the administration of enzyme-inducing agents causes increased rates of drug metabolism only 24-48 h after their administration.We wish to report in this paper an immediate and hitherto undescribed effect of hydrocortisone on rates of antipyrine elimination in man.

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

Interindividual variation and drug interactions with hormonal steroid contraceptives.

Large interindividual differences occur in the plasma concentration of contraceptive steroids. With the present tendency to decrease the dose of progestagen and oestrogen any factor which reduces the bioavailability of the lower dose preparations becomes very important. The possibility that other drugs and environmental chemicals may interact with contraceptive steroids is currently being investigated. Clinical reports suggest that the most important interacting drugs are the antituberculosis agent rifampicin, anticonvulsants and antibiotics. In the case of the first two, evidence is available suggesting that microsomal enzyme induction, either in the liver or the gut wall, is the operative mechanism. Antibiotics interfere with the pharmacokinetics of contraceptive steroids by interfering with their enterohepatic circulation in animal species: whether this is operative in man is still unclear. Other environmental and constitutional factors such as smoking, variations in diet, and concurrent disease may alter the disposition of contraceptive steroids and affect response accordingly. Additional studies are needed to estimate the significance of such interactions.

PIP: There has been little study on the clinical pharmacology of OCs (oral contraceptives). Studies have shown that large interindividual differences occur in the plasma concentration of contraceptive steroids, indicating a difference in metabolism. As estrogen and progestogen content of OCs are being continually lowered, any substance which reduces the bioavailability of the steroids within OCs may actually lower contraceptive efficacy also. The literature is studied for mention of drug and other environmental chemical interactions with OCs. 3 main groups of drugs have been shown to react adversely with OCs: 1) antituberculous drugs, especially rifampicin; 2) anticonvulsant drugs; and 3) antibiotics. Studies on all 3 of these types of drugs are cited along with advice to patients concerning each category of drug. For the 1st 2 types of drugs, microsomal enzyme induction in either the liver or the gut wall is the operative mechanism. Antibiotics interfere with enterohepatic circulation in animal species. It is believed that smoking and diet may also affect the efficacy of OCs. Probably only individuals with low plasma concentrations of the contraceptive steroids are at serious risk from drug and environmental interactions.

An investigation of the effects of phenobarbitone on the pharmacokinetics of norethindrone in the rat using liver perfusion and everted gut sacs.

Previous in vivo studies have suggested that phenobarbitone increases the first pass clearance of norethindrone in the rat by induction of enzymes both in the gut wall and liver. In the present study phenobarbitone caused an increase in both the production of highly polar ether-extractable metabolites and the conjugation of the steroid as it crossed the wall of the everted gut sac preparation. In addition, there was a marked increase in the uptake of norethindrone into the liver followed by increased phase I metabolism in the isolated perfused liver. As expected for a highly cleared drug, enzyme induction had no measurable effect on the terminal half-life of norethindrone in the perfused liver preparation.

The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite.

The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.

The in-vitro mucosal conjugation of ethinyloestradiol and the bioavailability of oral contraceptive steroids in patients with treated and untreated coeliac disease.

The ethinyloestradiol (EO2) component of oral contraceptive steroids is extensively conjugated with sulphate by the gut wall. The ability of gastrointestinal mucosa to conjugate EO2 has been examined in vitro in samples of mucosa taken from normal women as well as from women with coeliac disease. The percentage conjugation per mg dry weight for normal tissue (n = 11) was 17.1 +/- 6.4 (mean +/- s.d.) while in untreated coeliac tissue (n = 6) the figure was 6.3 +/- 3.6% (P less than 0.01). In tissue from patients with treated coeliac disease (n = 5) the figure was 12.1 +/- 3.2%. Thus the ability of intestinal mucosa to conjugate ethinyloestradiol was significantly reduced in patients with coeliac disease, and restored towards normal following treatment. However, in patients with coeliac disease the pharmacokinetics of ethinyloestradiol were not significantly different from normal controls.

PIP: Physicians took several small intestinal mucosal samples from female patients with or with out celiac disease at the Royal Liverpool and Broadgreen Hospital in Liverpool, England, to determine in vitro the mucosa's ability to metabolize ethinyl estradiol and levonorgestrel. They compared this in vitro ability with the pharmacokinetics of the 2 steroids in 5 women with celiac disease. The percentage conjugation of ethinyl celiac mucosa (17.1% mg dry weight vs. 6.3% mg dry weight; p .01); it was also greater than it was for celiac mucosa from patients treated with a gluten-free diet (12.1% mg dry weight; p .05). The percentage of conjugate as sulphate was 85% for untreated celiac mucosa. Among the 5 celiac disease patients, no significant differences in any of the pharmacokinetic parameters for levonorgestrel or ethinyl estradiol existed between pre- and post-gluten free diet treatment. These parameters included area under the curve, volume of distribution, and bioavailability. The physicians were able to compare the in vitro ability of intestinal mucosa to metabolize ethinyl estradiol with 1st in vivo pharmacokinetics in 2 patients. In both cases, the in vitro mucosal conjugation rose while the in vivo bioavailability fell (4.4% to 12.1% and 75.4% to 43.2% for patient 1, and 3.6% to 9.1% and 86.7% to 55.2% for patient 2). These findings suggest that celiac disease weakens the ability of intestinal mucosa to conjugate ethinyl estradiol, but a gluten-free diet can adequately improve this ability.

Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Pharmacokinetics of low-dose intravenous pethidine in patients with renal dysfunction.

The kinetics and elimination of pethidine (meperidine) after intravenous administration (150 micrograms/kg) to ten healthy volunteer subjects were compared with those obtained from 18 patients who suffered from varying degrees of renal dysfunction. In both groups of subjects, pethidine was eliminated triexponentially from plasma. However, plasma concentrations in the patients (who were subdivided into patients with severe dysfunction, moderate dysfunction, and mild dysfunction) were consistently higher. The mean +/- SEM elimination half-life (t1/2) of pethidine was significantly longer in the three groups of renal patients: 7.9 +/- 1.1, 20.2 +/- 13.6, 16.6 +/- 5.4, and 14.3 +/- 3.1 hr, respectively, for healthy volunteers, patients with severe, moderate, and mild dysfunction; their mean +/- SEM creatinine clearances were 97.3 +/- 7.5, less than 9.5, 30.0 (3.7), and 63.3 +/- 8.5 mL/min respectively. The mean plasma clearance of the drug was higher in healthy subjects (342.7 +/- 62.5 mL/min) than various groups of renal patients (99.9 +/- 11.6, 120.9 +/- 45.8, and 123.8 +/- 34.1, respectively, for patients with severe, moderate, and mild dysfunction). Impairment of renal function also reduced total plasma protein binding: 58.2 +/- 5.0% in healthy subjects and 31.8 +/- 3.9%, 44.5 +/- 5.0%, and 42.5 +/- 5.6%, respectively, for the three renal patient groups. The percentage of pethidine recovered in the urine was significantly lower in the severe dysfunction group while norpethidine recovery was significantly lower in all three groups of renal patients.(ABSTRACT TRUNCATED AT 250 WORDS)