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Acid secretion was measured after a six-week standard treatment with cimetidine in ten patients each with healed or non-healed duodenal ulcer, and the drug's pharmacokinetics studied. There was no difference between the two groups with respect to fasting concentration of cimetidine (compliance), the area under the plasma-level curve, as well as renal excretion (bioavailability) and the period of effective plasma concentration. Maximal secretion during cimetidine treatment was also identical in the two groups. On the other hand, basal secretion in the group of treatment failure was significantly increased (P less than 0.05). Basal secretion during administration of cimetidine can be used as a prognostic criterion for the healing of duodenal ulcer.

There are conflicting data on the existence of significant first-pass metabolism of alcohol (ethanol) in the human stomach and its inhibition by histamine H2-receptor antagonists. Alcohol is predominantly metabolised in the liver by the microsomal alcohol oxidising system, alcohol dehydrogenase (ADH) and a catalase enzyme. Histochemical and kinetic studies have revealed several ADH isoenzymes in the gastric mucosa with different kinetic properties. After small oral doses of alcohol first-pass metabolism in the stomach occurs, as shown by reduced area under the plasma concentration-time curve (AUC) compared with intravenous or intraduodenal administration. The activity of gastric ADH is reduced in women, the elderly, Asian individuals, the fasting state, chronic alcoholism and after gastrectomy. The effect is only present with small (or = 0.3 g/kg) alcohol doses and with a high alcohol concentration. In a number of studies, cimetidine in therapeutic doses over 7 days produced a significant increase in the AUC and in the peak plasma concentration after administration of alcohol 0.15 and 0.30 g/kg. This was related to an inhibition of gastric ADH activity, as shown by in vitro studies. Ranitidine inhibited gastric ADH to a similar extent on a molar basis, but its effect on alcohol levels in vivo was less constant in various studies. Nizatidine also reduced gastric alcohol first-pass metabolism, but famotidine and roxatidine did not show this effect. In other studies, H2-receptor antagonists did not change AUC and peak alcohol concentration. The controversy is not easy to resolve, since a number of the positive studies did not use a placebo-controlled, randomised, crossover design, while some of the negative studies did not exclude habitual alcohol consumers and included Oriental volunteers, although both groups have been shown to lack significant gastric ADH activity. In this case, when first-pass metabolism of alcohol does not exist, this by definition cannot be abolished by H2-antagonists. The inclusion of oral and intravenous dosage data of alcohol is mandatory to positively identify first-pass metabolism in any individuals. The significance of the effect of H2-antagonists on blood alcohol concentrations is minor. It only occurs in young, male, nonalcoholic, non-Asian individuals, and alcohol must be given in a small (social) dose, in a high concentration, and after meals. An increase in alcohol levels in predisposed patients during treatment with some H2-antagonists cannot be excluded, although the likelihood is small. Furthermore, carefully designed studies are needed to clarify fully the significance of this interaction.

Reactive oxygen radicals such as Superoxide and hydroxyl radicals, as well as intermediate unsaturated fatty acid radicals, have been proposed as playing an important role in various diseases including inflammatory bowel disease (IBD). In this study we evaluated radical scavenger properties of aminosalicylates used in the therapy of IBD using spin trapped electron spin resonance spectroscopy. 5-Aminosalicylic acid (5-ASA), 4-aminosalicylic acid and olsalazine had Superoxide radical scavenger properties ( ic 50 = 0.4, 0.4 and 1.0 mM , respectively). 5-ASA and benzalazine also inhibited hydroxyl radicals ( ic 50 = 6.5 mM ). Fatty acid radicals were not inhibited by aminosalicylates. Our results support the hypothesis that therapeutically active compounds may be oxygen radical scavengers and that fatty acid radical scavenging has to be performed by drugs other than aminosalicylates.

Since a previous review by Hurwitz was published in 1977 a large number of reports on drug interactions with antacids have appeared, few of which are of clinical relevance. Tetracyclines form insoluble complex molecules by metal ion chelation with various antacids; tetracycline absorption may be decreased by more than 90% by this interaction. Of the new class of quinolone antibiotics, the absorption of ciprofloxacin and ofloxacin is reduced by 50 to 90% in the presence of aluminium- and magnesium hydroxide-containing antacids. In contrast to early work showing inhibition of the absorption of beta-adrenergic blocking drugs by antacids, subsequent studies did not confirm a reduction in the bioavailability of either atenolol or propranolol during antacid treatment; indeed, they showed an increase in the plasma concentrations of metoprolol when the drug was coadministered with an antacid. The bioavailability of captopril was significantly reduced in the presence of an antacid, and lower plasma concentrations of this angiotensin-converting enzyme inhibitor were accompanied by a reduction of its effect on the systolic blood pressure of the patients. The absorption of the cardiac glycosides digoxin and digitoxin is not inhibited by antacids to a significant degree, although earlier studies had shown a positive effect when the dissolution of the glycoside preparations was relatively poor. Antacids reduce the bioavailability of the H2-receptor antagonists cimetidine and ranitidine only when high antacid doses are used and when the drugs are administered simultaneously. The bioavailability of famotidine was not significantly altered by a potent antacid preparation, although a trend towards reduced absorption was observed. Iron absorption is significantly decreased in the presence of sodium bicarbonate and calcium carbonate, but is nearly complete when coadministered with aluminium-magnesium hydroxide. Nonsteroidal anti-inflammatory drugs such as naproxen, tenoxicam, ketoprofen, ibuprofen and piroxicam are not affected in their absorption by antacid treatment. Theophylline bioavailability is unchanged when the drug is given together with antacids, although its rate of absorption may be altered, leading to a reduction or an increase in the time of the occurrence of peak plasma drug concentrations.

Reactive oxygen species such as superoxide radicals have been proposed to play an important role in the pathogenesis of inflammatory bowel disease. Some of the antiinflammatory actions of aminosalicylates have been ascribed to their capability to scavenge superoxide radicals directly or to inhibit its production in stimulated neutrophils. However, as a controversy still exists with regard to the precise mechanisms of inhibition and the metabolism within inflammatory cells, we compared scavenger properties of 5-aminosalicylic acid, 4-aminosalicylic acid,N-acetyl aminosalicylic acid, olsalazine, and benzalazine in systems with defined superoxide radical generation such as the dimethyl sulfoxide-NaOH and the potassium superoxide system. We also studied possible inhibition of the superoxide production following different stimuli of the respiratory burst in neutrophils and investigated the uptake and potential metabolism (N-acetylation) of 5-aminosalicylic acid in lipopolysaccharide-primed and resting neutrophils. We found that 5-aminosalicylic acid and 4-aminosalicylic acid had defined scavenger properties in the dimethyl sulfoxide-NaOH or potassium superoxide systems, respectively, whereas compounds with a modified aminophenolic structure had no effects. At the cellular level, 5-aminosalicylic acid inhibited phorbol myristate acetate (100 ng/ml)-activated superoxide generation to 82.3±9.3%, the formylmethionyl leucyl peptide (10−5 M) to 61.0±6.8%, and the NaF (20 mM) -stimulated production to 32.3±3.2% (X±sd,P

Warfarin and diphenylhydantoin (DPH) were displaced from plasma proteins in rats by in vivo elevation of free fatty acids (FFA) produced by exercise or by i.p. injection of d,l-epin

In a prospective trial 37 duodenal ulcer patients were treated daily with 1 g cimetidine. Personal and clinical data were obtained for all patients, acid secretion studies performed before and during treatment, and pharmacokinetic parameters of cimetidine determined. The healing rate after 4 weeks was 64.9% (24 patients). Non-Responders included a higher proportion of smokers, patients with a history of ulcer and previous treatment with H2-receptor antagonists than Responders. Basal acid output (BAO) and peak acid output (PAO) values were not different between the two groups, nor was the reduction of BAO and PAO under cimetidine. However, more Responders had complete suppression of BAO than Non-Responders. A correlation existed in both groups between cimetidine plasma concentration and PAO suppression but not with BAO suppression. Regular drug intake (compliance) was found in about 90% in both groups. Cimetidine bioavailability parameters were identical in both groups, but Non-Responders had a higher peak concentration and a shorter time of peak concentration. Discriminant analysis enabled a prediction of treatment response in 89.2% of the patients by using five factors: time of peak concentration of cimetidine, previous H2-receptor-antagonist treatment, peak concentration, smoking, and alcohol use. Prediction of treatment response is increased by use of drug related variables.

The pharmacokinetics of cimetidine (10 mg/kg) were investigated in 11 children following an oral dose and in 9 children following an intravenous dose. The children ranged in age from 4-13 years and were undergoing radiology for upper gastrointestinal tract pain. Compared with a group of adults, the children had a higher total body clearance (11.6 +/- 3.4 versus 7.0 +/- 2.5 ml/min per kg; P less than 0.005), a larger apparent volume of distribution (1.24 +/- 0.40 versus 0.80 +/- 0.24 l/kg; P less than 0.005) and a shorter elimination half-life (83 +/- 26 versus 122 +/- 16 min; P less than 0.001) of cimetidine. Renal clearance in children comprised 70% of total body clearance, more than double that of adults (9.0 +/- 1.9 versus 4.2 +/- 2.1 ml/min per kg; P less than 0.001). The area under the cimetidine plasma concentration: time curve after the oral dose was on average 42% in children compared with adults. The mechanism for the increased elimination of cimetidine in children is suggested to be an increase in the renal tubular secretory transport of cimetidine in the kidney. A statistically significant negative correlation was observed between age and cimetidine renal clearance. A cimetidine dosage regimen of approximately 30 mg/kg per day in three to four divided doses would be an appropriate dose in children.

Single-dose kinetics of 0.1 mg/kg intravenous diazepam, 10 mg/kg oral antipyrine, and 300 mg oral phenytoin were followed in healthy subjects before and after 400 mg metronidazole twice a day for 5 days. When data before metronidazole dosing were compared with those after metronidazole dosing, there were no changes in total plasma clearance of diazepam (0.53 and 0.65 ml/min/kg), antipyrine (39.0 and 38.0 ml/min/kg), or phenytoin (0.56 and 0.55 ml/min/kg). Plasma t 1/2s and volumes of distribution of the three drugs tested were not affected by metronidazole, but urinary excretion of 4-hydroxyantipyrine decreased after metronidazole dosing. There was no change in the elimination of phenytoin as its hydroxylated metabolite after metronidazole. It is concluded that, at therapeutic concentrations, metronidazole does not significantly inhibit oxidative drug metabolism.

The pharmacokinetics and bioavailability of cimetidine after 200 mg given intravenously and orally was studied in 6 gastric and 6 duodenal ulcer patients aged between 28 and 64 years. There were no differences in any of the pharmacokinetic parameters between the two ulcer groups, but there was considerable variation which was mainly age-related. Bioavailability was not complete, but was about 60% based on the plasma concentration data. The volume of distribution at steady-state was about 80% of body weight, and the plasma clearance value of 495 ml/min was mainly due to renal clearance (293 ml/min). The elimination half-life was approximately 2 hours. These pharmacokinetic parameters together with the percentage of dose excreted unchanged in urine following intravenous administration were all highly age correlated; all decreasing with age except the elimination half-life which increased with age. Of clinical importance is the finding that the time for which the plasma concentration exceeded 0.5 microgram/ml following oral administration was also highly age-dependent, increasing by more than 2-fold in the elderly (53 to 64y) compared with the younger (28 to 45y) patients.

In a randomized double-blind multicenter trial, 15 outpatients with endoscopically proved anastomotic ulceration after Billroth I or Billroth II partial gastrectomy received cimetidine, 1 g daily over eight weeks, or a placebo. All patients also received antacid. The ulcer healed completely in all seven cimetidine-treated patients and in one of the eight placebo-treated patients (P

The influence of a 7-day medication of either cimetidine (1,000 mg per day) or ranitidine (300 mg per day) on serum ethanol concentrations after a single oral dose of ethanol (0.8 gm per kg body weight) was investigated in a randomized placebo-controlled study in eight male volunteers. Compared with the placebo, cimetidine but not ranitidine produced a significant increase in both the peak serum ethanol concentration (85.9 ± 3.5 vs. 73.0 ± 3.2 mg dl−1, p < 0.02) and in the area under the serum ethanol concentration time curve (350 ± 19 vs. 304 ± 25 mg dl−1 hr−1, p < 0.05). However, the ethanol elimination rate was not affected by cimetidine. When ethanol (1.0 gm per kg body weight) was administered intravenously, cimetidine failed to induce a change in ethanol metabolism. Furthermore, the effect of H2-receptor antagonists was studied in animal experiments. Female Sprague-Dawley rats received a single dose of ethanol (7 or 3 gm per kg body weight) together with an intraperitoneal injection of either cimetidine (120 mg per kg body weight), ranitidine (120 mg per kg body weight) or isotonic saline. After alcohol absorption, ethanol elimination was significantly inhibited by both cimetidine (3.99 ± 0.39 vs. 5.68 ± 0.23 mmoles kg−1 hr−1, p < 0.02) and ranitidine (4.21 ± 0.14 vs. 5.68 ± 0.23 mmoles kg−1 hr−1, p < 0.02) at high ethanol concentrations (60 to 20 m M) but not at blood ethanol concentrations below 20 m M. These results suggest an increase in ethanol absorption due to cimetidine but not to ranitidine in man at ethanol serum concentrations below 20 m M. At ethanol serum concentrations above 20 m M, both H2-receptor antagonists inhibit ethanol elimination in the rat suggesting inhibition of microsomal ethanol oxidation.

The effect of cimetidine on hepatic clearance of the benzodiazepine derivative nitrazepam was evaluated in healthy subjects. Six received a single 5- or 10-mg oral nitrazepam dose in the drug-free state and again with therapeutic cimetidine doses. Nitrazepam kinetics were determined from multiple serum concentrations measured during the 72 hr after each dose. Cimetidine had no effect on nitrazepam absorption kinetics, since peak serum nitrazepam concentration and time of peak concentration were not altered. Cimetidine did not alter nitrazepam volume of distribution, but cimetidine consistently reduced nitrazepam clearance, from a mean of 1.41 ml/min/kg in the control state to 1.17 ml/min/kg during cimetidine treatment. This resulted in prolongation of nitrazepam elimination t½ from 22.2 to 27.8 hr. Thus the ability of cimetidine to impair drug oxidation in man extends to the capacity for clearance of nitrazepam, a compound biotransformed mainly by nitroreduction. Clinical Pharmacology and Therapeutics (1983) 34, 227–230; doi:10.1038/clpt.1983.157

A rapid gas chromatographic method is described for the determination of chlorophenoxyisobutyric acid (the active metabolite of clofibrate) in plasma and urine. The assay involves an extraction into toluene and back-extraction of the chlorophenoxyisobutyric acid and the internal standard (2-naphthoic acid) into the methylating reagent (trimethylanilinium hydroxide). Concentrations of 1 μg/ml in plasma and urine can easily be measured; the precision of the method is 3.3 ± 0.7% for plasma and 2.7 ± 0.4% for urine. There is no interference from endogenous compounds or from drugs commonly prescribed together with clofibrate.

The kinetics of chlorphenoxyisobutyric acid (CPIB) were studied in 5 healthy subjects after single 500-mg, 1,000-mg, and 2,000-mg doses of clofibrate, and in steady-state after 8 days' treatment with 1,000 mg twice daily. Maximum plasma concentrations of CPIB were observed 4 to 6 hr after dosing. A mean plasma half-life of 16.7 hr was recorded which was independent of dose and duration of treatment. Total plasma clearance (-Cl) calculated from area under the curve with the use of the total plasma concentration was 5.6 ml/min for the 500-and the 1,000-mg doses but increased to 6.8 ml/min for the 2,000-mg dose and was even higher (8.1 ml/min) in steady-state. This change in -Cl is a consequence of progressive reduction in the plasma protein binding of clofibrate at plasma concentrations above 50 microgram/ml, since -Cl rises in association with reduced protein binding at the high plasma concentrations measured after the 2,000-mg single dose and in steady-state. -Cl and apparent volume of distribution were identical for all doses tested when calculations were based on the nonprotein-bound CPIB concentrations only. Due to the inconsistant protein binding of CPIB, total steady-state concentrations could not be predicted from the single dose kinetic data.

1 The pharmacokinetics and bioavailability of cimetidine were studied after 200 mg oral and intravenous doses in 14 patients with liver cirrhosis, and results were compared to a control group of 12 ulcer patients. 2 In cirrhotic patients, the volume of the central compartment (0.41 +/- 0.06 v 0.19 +/- 0.09 1/kg) and the volume of distribution at steady-state (1.02 +/- 0.17 v 0.80 +/- 0.24 1/kg) were significantly increased. No differences were observed in the area volume of distribution, the total systemic plasma clearance and renal clearance. The non-renal clearance was significantly decreased from 191 +/- 46 to 123 +/- 102 ml/min. 3 The bioavailability of cimetidine (area method) was significantly increased from 60 +/- 23% to 77 /+- 18% in the cirrhotic patients. Also increased was the time during which plasma levels exceeded 0.5 microgram/ml. 4 Urinary excretion of cimetidine was increased in liver cirrhosis by 32% after intravenous and by 36% after oral administration, while the amount of the sulphoxide metabolite decreased accordingly. Creatinine clearance in the cirrhotic patients was highly correlated with the renal clearance of cimetidine as well as its total plasma clearance.

For drugs with a high hepatic clearance, bioavailability is low due to the so-called "first pass effect". Prediction of the bioavailability for these drugs has been only loosely tested. It is proposed that by plotting the reciprocal of bioavailability versus the oral clearance, a straight line with intercept of unity and slope of reciprocal of hepatic blood flow should ensue. For lignocaine and verapamil, this relationship was found to be strong and gave good predictability, whereas for propranolol this relationship was weak and gave poor predictability. The proposed method may be of value in determining whether the low bioavailability of a drug is due to hepatic first pass metabolism.

The pharmacokinetics of a single 300-mg oral and intravenous and 14 daily 300-mg oral doses of phenytoin were studied in 6 healthy volunteers. The mean plasma elimination t1/2 was the same following intravenous (16.8 +/- 1.3 hr) and oral (17.1 +/- 1.5 hr) doses of phenytoin; however, following chronic oral administration, the t1/2 increased to 18.9 +/- 1.5 hr (p less than 0.05). The absolute bioavailability of an oral dosage form (Dilantin Kapseals) varied from 57.7 to 85.6% when based on the relationship between the corresponding single dose areas under the curve (AUCs). When based on the comparison of the AUC for multiple oral dosing with the single iv dose area, average bioavailability was 85.9% (71.8 to 106.3). Since the variation in the bioavailability and elimination of phenytoin does not allow accurate prediction of the steady-state plasma concentration, monitoring plasma levels may be of special importance.

Since hypolipidaemic drugs are widely used, despite the still unanswered question whether lowering of plasma lipids has a protective effect on the development of atherosclerosis, discussion of the clinical pharmacokinetics of the main representatives of this group of drugs is warranted. Clofibrate is quantitatively transformed to its active metabolite, chlorophenoxyisobutyric acid (CPIB), immediately after oral administration. Absorption of CPIB is complete, but relatively slow with peak concentrations being attained 2 to 6 hours after the dose. The apparent volume of distribution is between 6 and 12 litres; plasma protein binding is higher than 90 %, but is reduced in the nephrotic syndrome, in renal failure, and in cirrhosis. The elimination half-life of CPIB ranges between 10 and 25 hours, is shorter in patients with the nephrotic syndrome, but is prolonged in renal failure in close correlation with the degree of renal impairment. The plasma clearance of the total drug (mean of 7ml/min) appears to be increased in the nephrotic syndrome, but is decreased in renal failure and is unchanged in liver cirrhosis. Clearance of the unbound drug (mean of 240ml/min) is markedly reduced in renal failure, but is also reduced in liver cirrhosis. No pharmacokinetic changes are observed in acute hepatitis. Urinary excretion of CPIB is normally 10 to 15% of the dose; excretion is reduced in renal failure, but is unaffected in the nephrotic syndrome and in liver cirrhosis. Nicotinic acid is rapidly absorbed with peak concentrations being attained after 45 minutes. The systemic availability is about 90 %. Accumulation of the drug is reported in red blood cells, but no information is available on its distribution and on its plasma protein binding. The plasma elimination half-life is about 45 minutes. One third of an oral dose is excreted in urine unchanged. With pharmacological doses the major metabolite is nicotinuric acid; other metabolites being N-methyl-nicotinamide, 2-pyridone, and 4-pyridone, respectively. A measurable pharmacological effect is achieved with plasma concentrations of 0.1 to 0.2μg/ml, while a therapeutic range of 0.5 to 1.0μg/ml is suggested. Flushing of the skin is reported to-occur only at the beginning of treatment when the plasma concentration of nicotinic acid increases. Several analogues of nicotinic acid have been developed with the intention of achieving a sustained effect by a gradual in vivo liberation of nicotinic acid. Cholestyramine is not absorbed from the gastrointestinal tract. As it is an anion exchange resin it may interfere with the absorption of a number of drugs by binding them to the resin. β-Sitosterol absorption is normally less than 5 %, but has been 25% in 2 sisters, so that a genetically determined influence on absorption is assumed. Dextrothyroxine possesses only a small fraction of the hypermetabolic activity of its levoisomer. Absorption is between 40 and 50%, but is decreased in malabsorption syndromes and in some patients with liver cirrhosis. Plasma protein binding is higher than 99 %. The elimination half-life is 6 to 7 days, but is decreased in hyperthyroidism and increased in hypothyroidism. Thyroxine is completely metabolised after oral dosing, une metabolite with pharmacological activity being triiodothyronine.

The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10-mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.

The introduction of fiberoptic endoscopy has altered the relative importance of ulcer symptoms in the diagnosis of peptic ulcer disease. Interestingly, we now realize that 50% of ulcer patients do not have the classical ulcer symptoms and that 25% of peptic ulcers are asymptomatic. Modern forward-viewing endoscopes of small diameter enable precise diagnosis with little discomfort in 95% of all duodenal ulcer patients. A biopsy is only recommended in rare cases (giant ulcers) because the malignancy rate is only 0.024% in duodenal ulcers. The diagnostic accuracy of endoscopy in detecting gastric ulcer is as high as that for duodenal ulcer, but for this ulcer type it is absolutely necessary to exclude malignancy by obtaining a minimum of six biopsies (four from the ulcer margin and two from the ulcer base), since approximately 10% of all gastric ulcers are actually carcinomas. Whereas in duodenal ulcer repeat endoscopy is seldom necessary, it is mandatory in gastric ulcer since ulcer healing is not proof of a benign ulcer. In experienced hands endoscopy is superior to radiography in duodenal and in gastric ulcer, although there is still a place for radiography as a supplementary investigation or if the patient rejects endoscopy. When selecting patients for treatment of peptic ulcer the following aspects must be considered: natural history of the disease, effectiveness of treatment, and risks and costs of treatment. Treatment goals (relief of symptoms, ulcer healing) can be achieved as far as the acute ulcer is concerned but as yet we have no evidence that we can cure chronic ulcer disease.

The O-deethylation of 7-ethoxycoumarin was inhibited in a mixed type manner by cimetidine in vitro and in microsomes isolated from rats treated with cimetidine in vivo. It was found that the inhibition was even greater if cimetidine was preincubated with the microsomal suspension in the presence of an NADPH-generating system prior to the addition of substrate. In vitro the decrease in activity was accompanied by a decrease in cytochrome P-450 content. This decrease was unaffected by the addition of EDTA to the microsomal suspensions, eliminating the possibility that free radical production was responsible for the decrease in cytochrome P-450. The decrease in activity and cytochrome P-450 content following preincubation of microsomal suspensions with cimetidine could be attenuated if potassium ferricyanide was added to the suspensions. The deethylation activity and cytochrome P-450 content of liver microsomes prepared from cimetidine-treated rats was decreased compared to control animals. The activity and cytochrome P-450 content of microsomes from cimetidine- treated rats could also be restored if microsomes were washed with potassium ferricyanide prior to incubation with substrate. It is proposed that an intermediate complex of cimetidine and cytochrome P-450 could be involved in the inhibition of microsomal metabolism by cimetidine.

A 3′-phosphoadenylylsulphate:steroid sulphotransferase is localised in the 150 000 × g supernatant of normal human liver. The enzyme was purified 22-fold by (NH4)2SO4 precipitation, by gel filtration of the precipitate through Sephadex G-200 and by chromatography on DEAE-cellulose. After incubation of the enzyme with dehydroepiandrosterone as substrate, the reaction product isolated was identified as dehydroepiandrosterone sulphate by paper chromatography, various micro-chemical reactions and crystallization with authentic carrier to constant specific activity. The sulphotransferase showed a pH optimum at 7.4 in Tris-HCl buffer. The Michaelis-Menten constants were found to be 6.7·10−6 M for dehydroepiandrosterone and 4.0·10−6 M for 3′-phosphoadenylylsulphate. The enzyme lost its activity within 6 days when stored at 4°; however, at −20°, the enzyme was stable for at least 4 months. The steroid sulphotransferase showed a temperature optimum at 50° and an activation energy of 22.2 kcal/mole, within the range of 37–50°. By gel filtration, using Sephadex G-200, the molecular weight of the sulphotransferase was found to be approximately 50 000. The activity of the purified enzyme preparation was not influenced by the addition of cystein or EDTA. In relatively high concentration, SH-blocking agents had an inhibitory effect. The addition of Co2+, Ni2+, Ca2+ and Mn2+ activated the enzyme, whereas Cu2+, Zn2+, Fe2+ and Hg2+ inhibited the sulphotransferase. The steroid sulphotransferase from human liver conjugates not only dehydro-epiandrosterone (100%), but also (although to a lower extent) 3α-hydroxy-5β-androstan-17-one (45%), oestriol (31%), oestradiol-17β (15%) and oestrone (8%). Testosterone and cholesterol were not conjugated by the enzyme.

An S-adenosylmethionine:catechol-O-methyltransferase (EC 2.1.1.6) is localised in the 150 000 × g supernatant of human placenta. The enzyme was purified 66-fold by (NH4)2SO4 precipitation and by repeated filtration of the (NH4)2SO4 precipitate through a Sephadex G-100 column. After incubation of epinephrine and S-[Me-14C]-adenosylmethionine, the main metabolite was identified as metanephrine (3-O-methyl-adrenalin). In the pH range of 6–8, the activity of the enzyme increased steadily. The Michaelis-Menten constants were found to be 43.5·10−5 M for epinephrine and 7.8·10−5 M for S-adenosylmethionine. The purified catechol O-methyltransferase was active for more than 3 months when stored at −20°. The enzyme shows a temperature optimum at 50° and an activation energy of 17.3 kcal/mole within the range of 24–42°. By gel filtration, using Sephadex G-100, the molecular weight of the placental catechol O-methyltransferase was found to be 52 000. The purified enzyme preparation was only active in the presence of cysteine (20–80 mM). In addition to epinephrine, other catechols were also methylated. When 2-hydroxyoestradiol-17β was used as substrate, 2-methoxyoestradiol-17β as well as 2-hydroxyoestradiol-17β 3-methyl ether were formed as metabolites. The methylation of epinephrine to metanephrine was inhibited competitively by 2-hydroxyoestradiol-17β.

infarction is not known. Moreover, the diagnosis of this arrhythmia should not be restricted to instances where delayed repolarization or extreme bradyarrhythmias are present. The therapeutic implications of this finding are unclear. Antiarrhythmic agents which potentially prolong the QT interval may be relatively contraindicated in this setting and the use of bretylium or early ventricular pacing may be preferable.

Clofibrat wird haufig zur Behandlung verschiedener Typen der Hyperlipoproteinamie eingesetzt, da es eines der wirksamsten Medikamente zur Senkung des Serumcholesterin-und Triglyceridspiegels bei Menschen ist. Ob allerdings die Herabsetzung der Lipide im Serum mit einer geringeren Mortalitats- oder wenigstens Morbiditatsrate bei Patienten mit Hyperlipoproteinamie einhergeht, ist ein schwieriges und noch nicht vollig gelostes Problem. Wir haben in fruheren Arbeiten gezeigt, das bei Hypalbuminamie im Rahmen eines nephrotischen Syndroms die Plasmaeiweisbindung von Clofibrat reduziert ist und die Plasmaclearance erhoht ist. Patienten mit signifikanter Niereninsuffizienz wurden bei der damaligen Studie von der Untersuchung ausgeschlossen, um den Effekt der eingeschrankten Nierenfunktion auf die Disposition von Clofibrat auszuschalten [1].

In 8 healthy subjects the absorption of cimetidine was investigated when given alone, together with 60 ml aluminium/magnesium hydroxide containing antacid (neutralising capacity 26 mmol HCl/10 ml), and together with liquid metoclopramide 14 mg. The antacid significantly (P less than 0.01) reduced the bioavailability (area under the plasma level-time curve) of cimetidine, on average by one third. Metoclopramide also reduced the bioavailability by an average of 22%. The reductions were associated with significantly reduced excretion of cimetidine in urine. There was no change in the half-life or renal clearance of cimetidine, supporting the hypothesis of reduced gastrointestinal absorption. The results indicate that cimetidine and antacids should not be given together, and that the dose of cimetidine may have to be increased if it is administered concomitantly with metoclopramide.

The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9 +/- 2.6 h in the single dose and 17.3 +/- 3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064 +/- 0.0011 l/kg X h. The apparent volume of distribution was small at 0.15 +/- 0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3 +/- 13.0 microgram/ml. Css observed was lower than Css predicted (99.2 +/- 14.7 microgram/ml) from single dose kinetics (p less than 0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7 +/- 0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.

To evaluated whether knowledge of plasma levels of anti-epileptic drugs has an effect on therapeutic outcome, 127 epileptic outpatients were randomly assigned to two groups (A and B). Plasma levels of group A were reported to the treating physician who attempted to keep the plasma levels within the "therapeutic range." The treating physician was not informed of the results of plasma level determinations of group B. Data from 105 patients were available for assessment at the end of the study year. Therapeutic results of groups A and B were not significantly different. The reduction in seizure frequency was associated with an increase in plasma concentrations of the anti-epileptic drugs. Thus, under the conditions of the study, knowledge of plasma levels of anti-epileptic drugs did not further improve therapeutic results.

Because of widespread (and often uncritical) use of Cimetidine, there is considerable potential for interactions to occur with other drugs. In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients. The absorption of ketoconazole was reduced by more than half with Cimetidine, a consequence of its poor water solubility which is enhanced in acid solution. Conflicting results are reported with tetracycline, the overall absorption of which does not appear to be significantly altered by Cimetidine. Aspirin absorption was halved by Cimetidine in 3 of 6 subjects, when the intragastric pH was raised above 3.5. Cimetidine did not affect the absorption of ampicillin, co-trimoxazole or prednisolone. Cimetidine has been shown to inhibit various microsomal drug-metabolising enzymes in animal as well as human liver, most likely through the binding of the imidazole ring structure of Cimetidine to the haeme moiety of cytochrome P-450. In 7 studies, Cimetidine uniformly prolonged antipyrine half-life by 18 to 37% and reduced its clearance by 10 to 27%. After chronic dosing with Cimetidine, warfarin clearance was reduced from 3.4 to 2.5ml/min, whilst the volume of distribution and elimination half-life remained unchanged. Steady-state warfarin concentrations, as well as Prothrombin times, increased upon addition of Cimetidine to the treatment regimen. Warfarin concentration and effect both returned to pre-Cimetidine values when Cimetidine was withdrawn. Amongst the benzodiazepines, diazepam, desmethyldiazepam and chlordiazepoxide plasma clearance values were reduced by Cimetidine by 43, 28 and 63 %, respectively, and half-lives increased accordingly, while volumes of distribution and protein binding were not affected. Long term treatment with Cimetidine and diazepam resulted in a 30 to 80% increase in steady-state diazepam concentrations. In contrast, the pharmacokinetics of oxazepam and lorazepam, which are eliminated almost entirely by glucuronidation and not oxidation, were not altered by Cimetidine. Cimetidine also inhibits the metabolism of phenytoin, theophylline and carbamazepine. A single dose of Cimetidine decreased indocyanine green clearance by 23%, which was interpreted as a reduction in hepatic blood flow. The area below the Propranolol concentration-time curve (oral administration) was increased by between 25 and 60 % with Cimetidine and by 25 % after intravenous administration of Propranolol, with no change in elimination half-life, volume of distribution or bioavailability. With chronic oral Propranolol dosing, Cimetidine increased the steady-state concentration from 23.2 to 44.9ng/ml. The bioavailability of labetalol almost doubled from 30 to 54 % with Cimetidine, with no change in half-life and systemic clearance. The oral clearance and elimination half-life of chlormethiazole was increased by 30 and 50%, respectively, by Cimetidine. Studies with high hepatic clearance drugs have not consistently shown cimetidine-induced changes in systemic clearance (liver blood flow dependent), but oral clearance increased in all cases, consistent with inhibition of drug metabolism. Peculiarities of Cimetidine effect on drug metabolism are (a) only about 20% of a Cimetidine dose is metabolised in man, as compared with a much larger fraction with other inhibitory drugs; (b) the maximum effect attained occurs within I day whereas offset of effect varies with individual interacting drugs; (c) the degree of inhibition of metabolism is much more pronounced in patients with already impaired liver function (i.e. liver disease). Antacids of a weak neutralising capacity (10 to 15mmol/dose) did not influence the absorption of Cimetidine. However, antacids (aluminium plus magnesium hydroxide) with a neutralising capacity between 26 and 41 mmol/10ml reduced the bioavailability of Cimetidine by 20 to 35%. A recent study with an aluminium plus magnesium hydroxide antacid of 70mmol/10ml did not affect Cimetidine bioavailability. The antacid preparation used differed from others by a disproportionate increase in the aluminium hydroxide content. Metoclopramide and propantheline also reduced the absorption of Cimetidine by an average of 20 %, indicating the importance of gastric emptying for Cimetidine absorption. Phenobarbitone administration over 3 weeks led to an increase in Cimetidine plasma clearance by 18%, mainly due to an increase in the non-renal clearance, but probably also partially due to a reduction in Cimetidine absorption. The most important clinical consequences of interactions with Cimetidine primarily involve inhibition of drug metabolism. Clinically important interactions are predominantly manifested in those drugs which have a narrow therapeutic index (e.g. Phenytoin, warfarin, theophylline). The interaction leads to higher steady-state blood concentrations and hence increases the incidence of side effects and toxicity. Adverse effects of such interactions can be avoided by careful monitoring and adjustment of dosage for those drugs which undergo phase I metabolic detoxification in the liver when it is necessary to administer such drugs concomitantly with Cimetidine.

Clinical pharmacological studies have contributed substantially to our understanding of drugs, in particular in the area of clinical pharmacokinetics. We are impressed by the enormous progress in the analytical methodology (GC, HPLC, mass spectroscopy) to an extent, that some simple aspects of clinical studies have been neglected in favor of newer and more sophisticated techniques. Consequently, characterization and selection of patients in published studies is often surprisingly poor and diminishes the quality of otherwise good clinical pharmacological data.

Clofibrat hat grose Bedeutung in der Behandlung verschiedener Formen von Hyperlipoproteinamie, da es eines der wirksamsten Medikamente zur Senkung des Serum-Cholesterin- und Triglyceridspiegels beim Menschen ist.

Cimetidine plasma concentration-response relationships were investigated in six healthy subjects using suppression of gastric acid secretion under continuous pentagastrin stimulation (1.5 micrograms/kg/hr) as a test model. With the Hill equation the sigmoid was preferable to the linear relationship between plasma concentration and effect, and there were significant correlations of 0.78 micrograms/ml (range 0.54 to 1.04 micrograms/ml) for 50% inhibition of gastric acid secretion was determined; mean concentration for 90% inhibition was calculated to be 3.9 micrograms/ml. The model described should allow determination of whether different patient populations (e.g., healthy subjects, patients with ulcers, male and female patients, patients with renal or liver disease) differ from one another in concentration-response relationships to histamine H2-receptor antagonists, so that appropriate drug plasma levels should be achieved for specific degrees of inhibition of gastric acid secretion.

Zunachst zwei Binsenwahrheiten: 1. Es gibt wesentlich mehr Arzneimittel als notwendig sind. 2. Der Arzt, unabhangig davon, ob Allgemeinarzt oder Facharzt, verschreibt nur eine begrenzte Zahl von Medikamenten, die in den meisten Fallen unter 100 liegt und selten uber 250 ansteigt.

The bioavailability of three commercial products of phenytoin (Epanutin, sodium salt; Phenhydan, calcium salt; Zentropil, free acid) was studied relative to a standard solution of sodium phenytoin. Each preparation was given for 14 days in a daily dose of 300 mg according to a cross over design. The three brands tested were equivalent as to their bioavailability with respect to plasma concentrations during one dosing interval, the area under the plasma level time curve, the time of peak plasma concentration, and the urinary excretion of the primary metabolite. Therefore, these phenytoin brands are bioequivalent and exchangeable for antiepileptic treatment. The standard solution of sodium phenytoin had a higher bioavailability as compared to the commercial products.

The effect of renal failure on the excretion of oral doses of practolol has been studied. The plasma half-life increased up to 6.6 times normal and the cumulative urinary excretion of the drug was reduced. There was a linear correlation between the overall elimination rate constant of practolol and inulin and creatinine clearances. A linear correlation was also found between the renal clearances of practolol and inulin. The dose of practolol required for maintenance therapy should be reduced in patients with impaired renal function.

In a double-blind multicenter trial, 100 patients with active duodenal ulcer were treated with a single nocturnal dose of famotidine 40 mg or ranitidine 300 mg. Antacid tablets were allowed as additional treatment if needed for pain relief. Endoscopy was repeated after two weeks, and again after four weeks if the ulcer had not healed earlier. Two patients in the famotidine group were withdrawn from the study because of non-compliance with the protocol. After two weeks, ulcers in 64 percent of the patients receiving famotidine and 46 percent of the patients receiving ranitidine were healed (p = 0.072). After four weeks, healing rates were 94 percent (famotidine) and 90 percent (ranitidine). Pain relief was rapid in either treatment group, with a tendency for better response during the day in the famotidine group. Mean antacid consumption during the first week was 3.0 tablets (34.5 mmol) in the famotidine group and 4.1 tablets (47.2 mmol) in the ranitidine group. Famotidine provides excellent healing and relief of symptoms in patients with duodenal ulcer disease.

Kinetics of metronidazole and its metabolites were examined after single oral and intravenous doses and multiple oral doses in seven subjects by a sensitive HPLC assay. After 400 mg metronidazole IV, mean Vdβ was 1.05 l/kg. Mean plasma t½ was 8.3 hr with a ClTBC of 1.31 ml/min/kg. Clearance to the major metabolites, 2-hydroxy-metronidazole and 1-acetic acid metronidazole, accounted for over 90% of the ClTBC. After a single oral 400-mg metronidazole dose, the development of peak metronidazole plasma concentrations of 6.9 μg/ml averaged 2.3 hr after dosing. Systemic oral bioavailability was complete (98.9%). During twice-daily multiple metronidazole dosing, 400 mg, metronidazole kinetics were the same. Elimination t½ was 8.3 hr and average predicted steady-state metronidazole concentrations during one dosing interval (6.3 ± 0.5 μg/ml; mean ± SE) were equal to the observed concentrations (6.9 ± 1 μg/ml). Urinary excretion of unchanged metronidazole was below 10% of the total dose. Seventy-five percent of the dose was 2-hydroxy-metronidazole and 1-acetic acid metronidazole, and 15% was conjugates of metronidazole and 2-hydroxy-metronidazole. Clinical Pharmacology and Therapeutics (1983) 34, 481–487; doi:10.1038/clpt.1983.201

The half-life of antipyrine in plasma was studied In four hyperthyroid and four hypothyroid patients before and after thyroid status returned to normal. The half-life (± S.E.M.) was 7.9 ± 1.0 hours In hyperthyroid and 17.3 ± 1.1 hours in hypothyroid patients. After correction of the abnormal thyroid state the half-life values of both groups (12.3 ± 0.7 and 12.0 ± 0.5 hours) were within the normal range. These results suggest that abnormalities of thyroid function can markedly influence human metabolism of some drugs. (N Engl J Med 290:1040–1042, 1974)

1. β-Receptor-blocking drugs are rapidly and completely absorbed after oral administration. Systemic availability is nevertheless incomplete for propranolol, alprenolol and oxprenolol, owing to ‘first-pass’ extraction by the liver. 2. Plasma half-life is between 2 and 4 h, except for sotalol (10–12 h). Plasma elimination of propranolol is reduced with decreased liver blood flow, observed in congestive heart failure or during chronic propranolol therapy itself. 3. β-Receptor blockade is usually achieved in these concentration ranges: propranolol and alprenolol, 50–100 ng/ml; oxprenolol, 500–1000 ng/ml; pindolol, 10–30 ng/ml; sotalol, 2–6 μg/ml. Higher concentrations are often found with high doses administered to hypertensive patients.

Nach i.v.-Infusion von 20 mg bei 6 Probanden fallt die Blutspiegelkurve zunachst rasch, im Sinne einer einfachen Exponentialen mit einer Halbwertzeit von 5.3±0.3 h ab. Dieser Wert ist erheblich langer als von Shand u. Mitarb. mit der fluorimetri- schen Methode bestimmt, und past auch sehr viel besser zu dem, was wir aus der Klinik uber das Abklingen der Betablockade wissen. Die Kurve lies sich durch eine entsprechende rechnerische Angleichung am besten durch die Summe zweier Expo- nentialterme beschreiben, so das ein Zweikompartimentmodell angewandt werden konnte. Die totale Clearance lies sich mit 380±30 ml/min berechnen. Das relative Verteilungsvolumen, berechnet aus der i.v.-Kurve, betragt 2.6±0.4 1/kg. Das bedeutet, das Propranolol in erheblichem Ausmas im Gewebe gespeichert wird. Nach oraler Verabreichung von 80 mg kam ein rascher Blutspiegelanstieg zur Darstellung, die Kurve erreichte nach etwa 3 h ihr Maximum und fiel dann ahnlich wie die i.v.-Kurve ab. Bei der Angleichung fiel auf, das die Invasion nicht linear verlauft, das uberrascht insofern, als bisher auch dieses Phanomen nicht beschrieben wurde. Aussagen uber die biologische Verfugbarkeit sind aus den hier dargestellten Experimenten nicht moglich, da bei der oralen Gabe eine grosere Dosis verabreicht wurde und die Resorption von Propranolol dosisabhangig ist.