U. Klotz

Disposition and first‐pass metabolism of ethanol in humans: Is it gastric or hepatic and does it depend on gender?

To assess the extent and site of the first‐pass metabolism of ethanol and to examine whether first‐pass metabolism and disposition of ethanol are dependent on gender.

Treatment of Crohn's Disease With Peroral 5-Aminosalicylic Acid

Eighteen patients with active Crohns disease entered an open trial with 5-aminosalicylic acid in a slow-release preparation. All had lesions of the small bowel. Ten of them also had Crohns disease of the colon. 5-Aminosalicylic acid, 500 mg three times daily, was administered for 6 wk. Even with meticulous monitoring, no side effects of any kind were observed, particularly no cases of renal affection, which could have been expected from animal studies. The clinical course was estimated as improved in 13 patients (72%), unchanged in 2 patients (11%), and aggravated in 3 patients (17%); 2 of these 3 were withdrawn from the study and switched to alternative treatment. The Crohns disease activity index decreased from a median of 226 points to 99 points. On the basis of these results, large-scale controlled therapeutic trails seem warranted in order to establish clinical evidence for the benefit of peroral treatment with 5-aminosalicylic acid in patients with Crohns disease.

Pharmacokinetics of lorcainide in man: a new antiarrhythmic agent.

SummaryA gas liquid chromatographic assay was developed to measure in plasma and urine concentrations of the new antiarrhythmic drug lorcainide, its dealkylated metabolite and an added internal standard of similar structure. The limit of sensitivity was 10ng/ml plasma. In 5 healthy volunteers and in 6 patients with ventricular premature beats (VPB) the pharmacokinetics were determined after a single intravenous dose of 100mg. In 4 of the patients with VPB, the disposition was also evaluated under steady-state conditions following oral administration of 100mg twice daily. In 4 of the healthy volunteers, the bioavailability of a single 100mg (n = 2) and 150mg (n = 2) oral dose was determined. In an additional crossover experiment, bioavailability of a single oral dose of 100 and 200mg was also measured in 2 patients with VPB.Less than 2% of the intravenous dose could be recovered as unchanged lorcainide in the urine, indicating extensive metabolism. The drug was bound to plasma proteins to the extent of 85.0 ± 5.0% (mean ± SD) in healthy subjects and 83.3 ± 2.9% in patients with VPB. Since the plasma levels declined biexponentially after an intravenous dose, data were analysed according to a 2-compartment open model. The elimination half-life (t1/2β) of 5.1 ± 0.6h (healthy subjects) was somewhat longer (p = 0.02) in patients with VPB (7.6 ± 2.2h), but total plasma or blood clearance were very similar; the latter approaching a normal liver blood flow of 1.5L/min. The apparent distribution volumes Vdβ (8.6 ± 2.4L/kg vs 10.7 ± 4.2L/kg) and Vdss(6.4 ± 2.4L/kg vs 8.8 ± 3.4L/kg) showed no statistically significant difference between the healthy subjects and patients.After oral doses, high and saturable first-pass hepatic metabolism seems to exist. The crossover experiments in 4 subjects indicated bioavailability of about 1 to 4.5 % after a single 100mg dose, between 7 and 20 % after a 150mg dose, and between 35 and 65 % after a 200mg dose. In contrast, 3 of 4 patients with VPB on oral maintenance therapy exhibited bioavailability of 100%. This indicates that lorcainide belongs to the group of drugs exhibiting non-linear elimination kinetics.

No Evidence of a Genetic Polymorphism in the Oxidative Metabolism of Midazolam

SummaryThe benzodiazepine midazolam is rapidly eliminated by oxidative metabolism. In young healthy volunteers elimination half-life (t½) is about 2.4 hours. A recent study showed a prolonged t½ from 8 to 22 hours in 6.5% of surgical patients, and a genetic polymorphism of midazolam’s metabolism has been suggested. Therefore, we measured in 168 surgical patients the elimination of midazolam and its major hydroxylated metabolite (α-OH-midazolam) in blood and urine. Co-medication, disease status, smoking habits and alcohol intake were recorded; normal liver and kidney functions were assessed by routine laboratory tests. Midazolam was administered intravenously (0.1 to 0.2 mg/kg) for the induction of anaesthesia. Blood was drawn 1.5, 3, 4.5 and 6 hours after application and urine was collected for 6 hours. Plasma protein binding of midazolam was determined by equilibrium dialysis. Midazolam and α-OH-midazolam were measured in plasma by specific gas-liquid chromatography and in urine by high performance liquid chromatography. Data for the dose-corrected area under plasma-level curve of midazolam (AUC-midazolam/dose: 1.23 ± 961 × 105 h/ml; mean ± SD) and for the metabolic plasma ratio (AUC of α-OH-midazolam/AUC-midazolam: 0.52 ± 0.28) demonstrated a log-normal distribution. Likewise, the percentage of the unbound fraction of midazolam in plasma (5.0 ± 2.4%), urinary excretion of α-OH-midazolam (55.9 ± 22.7% of dose) and the values for t½ (2.9 ± 1.1 hours) did indicate a unimodal distribution. Age, comedication and smoking habits did not affect the disposition of midazolam. However, patients with regular intake of alcohol had a higher (p < 0.05) metabolic ratio. Only in 3 patients could a prolonged t½ of midazolam from 7.5 to 10.2 hours be detected, but plasma levels and urinary excretion of α-OH-midazolam in those individuals were found to be normal. Therefore it is very unlikely that the oxidative metabolism of midazolam exhibits a genetic polymorphism.

Alterations in the disposition of differently cleared drugs in patients with cirrhosis.

We have compared the disposition of antipyrine orally (15 mg/kg) and the new antiarrhythmic drug lorcainide intravenously (1.5 mg/kg) in 8 patients with alcoholic cirrhosis. Antipyrine (AP) serves as a model drug for drugs which are eliminated independently of liver blood flow and lorcainide (L) elimination as a model for drugs which depend on liver blood flow. Since in healthy subjects elimination half‐life (t½) of L increased with age (r = 0.68, p < 0.01) due to parallel change in the volume of distribution (r = 0.52, p < 0.05), its disposition had to be compared to age‐matched controls. Elimination of both AP and L was impaired in cirrhotic patients, expressed either in terms (mean ± SD) of t½ (AP = 26.8 ± 15.0 hr and 12.3 ± 1.8; L = 12.5 ± 4.5 hr and 7.7 ± 2.2 hr, p = 0.002) or of clearance (Cl) (AP = 21.9 ± 7.9 ml/min and 41.7 ± 5.5 ml/min; L = 814 ± 144 and 1002 ± 304 ml/min, p = 0.06). While the alterations in plasma Cl were great for AP, they were smaller for L. This suggests that elimination of drugs in cirrhotic patients is associated with relatively more impairment of enzyme activity than of hepatic blood flow. The slightly decreased Cl of L in patients with alcoholic cirrhosis would suggest that L should be carefully handled in patients with dysfunction of the liver.

Renal function was not impaired by treatment with 5-aminosalicylic acid in rats and man

SummaryIn rat experiments and a clinical trial we have examined the suspected nephrotoxic potential of 5-amino-salicylic acid (5-ASA), the biological active metabolite of sulfasalazine (SZ). Male Wistar rats were treated orally for 4 weeks daily with 30 and 200 mg 5-ASA/kg and 75 and 500 mg SZ/kg. The two renal marker enzymes N-acetyl-β-D-glucosaminidase (NAG; EC 3.2.1.30), alanineaminopeptidase (AAP; EC 3.4.11.2) and creatinine were monitored in urine. At the end of the experiment rats were sacrificed, the removed kidneys histologically examined and drugs, their metabolites and creatinine measured in plasma and urine. In 9 patients treated chronically for their Crohns disease with 3×0.5 g 5-ASA daily in form of suppositories and an oral preparation urinary excretions of NAG, AAP and serum creatinine were also monitored before and during therapy. Neither the animal experiments nor the observations in patients gave any evidence of nephrotoxic lesions induced by 5-ASA. Thus, our data show that in the doses applied, 5-ASA was devoid of altering renal excretion in rats and man.

Lorcainide infusion in the treatment of ventricular premature beats (VPB)

SummaryThe plasma level and antiarrhythmic effect of lorcainide (R 15889) have been investigated in 15 patients with ventricular premature beats (VPB). Therapy was initiated with an intravenous dose of 1.9 mg/kg given over 10 min, followed by a constant infusion of 0.18 mg/kg/h for 24 h. In 8 patients the corresponding doses were increased to 2 mg/kg and 0.27 mg/kg/h. After the intravenous doses patients were treated orally with 100 mg tid for 6–7 days. The two dosage regimens were selected so as to achieve theoretical steady-state plasma levels (css) of 200 and 300 ng/ml, respectively. The combined intravenous treatment approached (181 ± 6.8 ng/ml and 273±28.5 ng/ml, respectively) the desired css within 2 to 4 h. During the oral administration, the minimal plasma concentrations following the lower intravenous dose (184±18 ng/ml) were significantly (p=0.0001) lower than after the higher intravenous dose (264±20.5 ng/ml). The dealkylated metabolite of lorcainide was not detectable after the intravenous doses, but it accumulated during oral treatment, when its concentration exceeded that of the parent compound. In 5 of the 7 patients receiving the lower dose VPB were effectively reduced. However, in only 4 of the 8 patients on the higher dosage schedule could a significant antiarrhythmic effect be demonstrated. In addition, side effects were observed in 6 of the subjects.

Expression of intestinal drug-metabolizing enzymes in patients with chronic inflammatory bowel disease

Abstract The cause of chronic inflammatory bowel disease (IBD) remains unclear. A recent hypothesis suggests that ulcerative colitis may be caused by one or more reactive xenobiotic metabolites. If so, the presence, distribution, and activity of drug-metabolizing enzymes in the gut could be important, because those enzymes represent a first defense against ingested xenobiotics. To assess whether patients with IBD express certain enzymes differently in the gastrointestinal tract than do subjects without IBD, biopsy samples of the terminal ileum and various regions of the colon were stained immunohistochemically for cytochrome P-450 (CYP) isoenzymes (CYP1A1, CYP2D6, CYP2E1, CYP3A), epoxide hydrolase, α and π forms of glutathione- S -transferase (GST), and metallothionein (MTTH). One hundred fifty biopsy samples from 21 patients with irritable colon (no clinical or histologic signs of inflammation; control group), 25 patients with Crohns disease (CD), and 37 patients with ulcerative colitis (UC) were evaluated. The patients sex, age, smoking habits, and disease state were not related significantly to the frequency of positive versus negative staining of the samples. All enzymes were expressed less frequently in the colon than in the terminal ileum. With the exception of CYP1A1, all enzymes were detectable with similar frequency in the three study groups: CYP2E1, 77.4% to 84.6% positive stainings; CYP3A, 53.8% to 58.5%; CYP2D6, 23.1% to 36.9%; GST α , 14.1% to 20.8%; GST π , 19.2% to 24.5%; epoxide hydrolase, 1.9% to 3.8%; and MTTH, 19.2% to 25.4%. However, CYP1A1 staining was positive significantly more often in patients with CD (39.6%) and UC (39.4%) than in patients in the control group (19.2%). Because cells with CYP1A1 were found in the intestines of patients with IBD significantly more frequently than in patients in the control group (ie, with an irritable colon), this may suggest a function of this enzyme in the etiology or pathogenesis of inflammation in these disorders. Alternatively, the more frequent expression of CYP1A1 could be due secondarily to the presence of xenobiotics that then lead to inflammation.

Effect of intravenous ketanserin on plasma catecholamines and renin activity in normal volunteers

SummaryIn a placebo controlled, single blind, randomized cross over study catecholamines (CA) and renin activity (PRA) in plasma were measured in 2 female and 4 male healthy volunteers, at rest in the supine position, following a single intravenous injection of 0.15 mg/kg ketanserin (K) and placebo (P, 10 ml saline). K caused a significant increase in the area under the plasma norepinephrine (NE) time curve (AUCNE) from 13,200 to 18,100 ng × 1−1 × min for 1 hour after the injection. The area under the plasma epinephrine (E) time curve (AUCE) was also increased but to a lesser extent; it was significantly elevated from 54 to 68 ng × 1−1 × min for 1 minute after the injection. Dopamine (DA) and PRA did not show any significant response to ketanserin. Following the P injection, none of the four parameters showed any significant change.

Flumazemil Disposition and Elimination in Cirrhosis

Flumazenil, a new and specific benzodiazepine antagonist that appears to be free of intrinsic pharmacologic action, is extensively metabolized by oxidative processes and represents a high-clearance drug. Consequently, it could be anticipated that hepatic disease affects the elimination and oral bioavailability of flumazenil. Therefore, the pharmacokinetics of flumazenil was evaluated in eight patients who had moderate cirrhosis and in eight age-matched healthy volunteers after a single oral dose (30 mg) and after an intravenous dose (2 mg). The mean half-life (t1/2) was 0.8 versus 1.4 hours (p = 0.003) and total plasma clearance was 1201 versus 705 ml per minute (p = 0.009) for control subjects versus patients with cirrhosis. Bioavailability increased from the normal 28% to 65% (p = 0.001) in patients with hepatic dysfunction. Routine liver tests did not correlate with the elimination of flumazenil in individual patients. It can be concluded that elimination of flumazenil is impaired in patients who have stable alcoholic cirrhosis. Despite the relative wide margin of safety of flumazenil, somewhat lower doses could be effective in such patients if long-term oral use is anticipated.