Rashmi V. Patwardhan

Cimetidine impairs elimination of chlordiazepoxide (librium) in man

We have studied chlordiazepoxide (Librium) disposition and elimination in eight normal subjects before and after 1 week of cimetidine therapy, 300 mg orally four times a day. Cimetidine strikingly impaired the clearance of chlordiazepoxide from plasma, and this was, at least in part, due to decreased demethylation of the drug to N-desmethylchlordiazepoxide. Since the volume of distribution of chlordiazepoxide was not altered by cimetidine, the elimination half-life of chlordiazepoxide was also significantly prolonged by cimetidine therapy.

Normal Metabolism of Morphine in a Cirrhosis

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.

Effect of Cimetidine and other antihistaminics on the elimination of aminopyrine, phenacetin and caffein

Abstract Cimetidine is widely prescribed for the treatment of peptic ulcer disease and has recently been shown to inhibit the metabolism of warfarin, antipyrine and diazepam. To further examine this phenomenon we investigated the effect of various doses of cimetidine and other related drugs on 14C-aminopyrine, 14C-phenacetin and 14C-caffeine breath tests. Cimetidine caused a dose-related inhibition of the metabolism of aminopyrine and caffeine but had no effect on the phenacetin breath test. Metiamide, H1-antihistamines, phenothiazines and local anesthetics also inhibited the aminopyrine breath test. Cyproheptadine had no effect on either phenacetin or caffeine elimination. This study demonstrates a complex drug-drug interaction which may have widespread clinical implications.

Impaired elimination of caffeine in cirrhosis.

The effect of cirrhosis on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 15 healthy controls and eight patients with cirrhosis. The elimination half-life was prolonged from 5.2±2.4 hr (mean±sd) in controls to 6.1±1.9 hr in cirrhotics, although this did not reach statistical significance. The plasma clearance, however, was significantly higher (1.4±0.5 ml/min/kg) in controls as compared to cirrhotics (0.9±0.3 ml/min/kg) (P<0.05). The plasma binding of caffeine was also lower in cirrhotics (31.3±1.8% vs 25.5±4.0%,P<0.01). The plasma clearance of unbound caffeine therefore was reduced from 2.0±0.8 ml/min/kg in controls to 1.2±0.4 ml/min/kg (P<0.01) in cirrhotics, demonstrating impaired elimination of caffeine in cirrhosis.

Mephenytoin hydroxylation deficiency: Kinetics after repeated doses

Deficient aromatic hydroxylation of S‐mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3‐methyl‐5‐(4‐hydroxyphenyl)‐5‐ethylhydantoin (4‐OH‐M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4‐OH‐M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 µCi of 14C‐S‐mephenytoin, 45 µCi of H3‐R‐mephenytoin, and 11.5 µmol/kg of both S‐ and R‐mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S‐enantiomer rapidly excreted as 4‐OH‐M and the R‐enantiomer slowly excreted as 5‐phenyl‐5‐ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation‐deficient subject, there was no evidence of stereoselective metabolism, recovery of 4‐OH‐M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S‐mephenytoin results in the S‐enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin.

Furosemide disposition in cirrhosis

Furosemide disposition after rapid intravenous injection (80 mg) was studied in 10 normal healthy subjects and eight patients with cirrhosis and ascites. In the cirrhotic patients the elimination half‐life was modestly longer (81.0 ± 8.0 min and 60.2 ± 5.8 min). This prolongation was not associated with a difference in systemic clearance (156 ± 7 ml/min in normal and 142 ± 16 ml/min in cirrhotic subjects), rather it was a reflection of alterations in furosemide distribution. The steady‐state volume of distribution was increased from 8.5 ± 0.4 l in the healthy subjects to 12.1 ± 1.3 l in the cirrhotic subjects; estimation in terms of unbound drug indicated an approximately 50% smaller value in cirrhosis. These observations were quantitatively consistent with the increased percentage of furosemide in plasma in the unbound form in the patients (10.2 ± 1.0%) compared to in the normal subjects (4.0 ± 0.1%). The 24‐hr percentage urinary recovery of unchanged drug (58.8 ± 2.8% and 53.1 6.5%) and the glucuronide metabolite (17.8 ±7.5 and 21.3 ± 3.4) were on the same order in the normal and cirrhotic groups. The lack of major effects of cirrhosis on furosemide disposition suggests that changes in furosemide diuretic efficacy in such patients is a result of altered dynamic factors rather than altered disposition.

Effects of caffeine on plasma free fatty acids, urinary catecholamines, and drug binding

The effects of caffeine (250 mg orally) on plasma free fatty acids (FFA), urinary catecholamines, and drug binding were studied in 16 normal subjects (six men, five women on oral contraceptives, and five women not on oral contraceptives). FFA doubled 1 hr after caffeine, and remained elevated for at least 4 hr, with elevation of each FFA. Urinary excretion of epinephrine and dopamine increased (p < 0.05) in the first 2 hr, returning to baseline in the next 2 hr. Plasma binding of chlordiazepoxide, diazepam, and propranolol was estimated in each of the hourly plasma samples after caffeine; there was no change in percent unbound drug in any of the samples. In vitro addition of oleic acid to plasma samples of four subjects caused a step‐wise increase in percent unbound fraction of all three drugs whereas in vitro addition of caffeine did not further alter drug binding. In our study circulating plasma FFA and urinary catecholamine levels were elevated after caffeine ingestion. In spite of a rise in FFA, there was, however, no change in plasma binding of chlordiazepoxide, diazepam, or propranolol.

Short-term ethanol administration impairs the elimination of chlordiazepoxide (Librium®) in man

SummaryEthanol may enhance the sedative effect of benzodiazepines leading to greater psychomotor impairment, but the mechanism is not clear. The present study was carried out to determine the effect of acute ethanol ingestion on the disposition and elimination of chlordiazepoxide (Librium), a widely used benzodiazepine. Five healthy, 22–39-year-old, male volunteers ingested ethanol 0.8 g/kg as 25% in orange juice 1 h before chlordiazepoxide 0.6 mg/kg was injected intravenously. To maintain plasma ethanol concentrations of 50–150 mg/100 ml for 32 h additional ethanol 0.5 g/kg was given orally every 5 h. Plasma clearance of chlordiazepoxide fell from 26.6±2.6 ml/min (mean±SD) without ethanol to 16.6±3.1 ml/min (P<0.05) after ethanol. There was no change in the volume of distribution and therefore the elimination half-life was prolonged from 7.1±1.9 h to 11.8±6.0 h (P<0.05) after ethanol. Ethanol also lowered the plasma binding of chlordiazepoxide from 94.7± 0.6% to 93.4±1.3% (P<0.05). The plasma clearance of unbound chlordiazepoxide fell from 468± 51 ml/min to 264±98 ml/min (P<0.05) after ethanol. The plasma level of the metabolite desmethylchlordiazepoxide was higher and its elimination slower after ethanol. Thus using a pharmacokinetic approach this study has demonstrated that short-term ethanol ingestion in moderate doses impairs the elimination of chlordiazepoxide and accounts, at least partly, for the greater sedation that results when ethanol is taken concomitantly.

Differential effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism in the rat

The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P less than 0.05) whereas in vivo N-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-Demethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P less than 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants, Km, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P less than 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448 mediated drug metabolism, with a greater effect on the former microsomal system.

554 FETAL ALCOHOL SYNDROME: A MECHANISM FOR GROWTH RETARDATION

Growth retardation (GR) is a principle feature of Fetal Alcohol Syndrome (FAS). GR is of prenatal onset and generally there is no postnatal catch-up growth. Since Zinc (Zn) is an essential element for protein synthesis and growth during the critical prenatal and postnatal periods, we postulated that ethanol (E) may interefere with placental Zn transport. Therefore, we studied the effect of both acute and chronic (E) ingestion during pregnancy on in vivo placental Zn transport in pregnant rats. Two groups of pregnant rats were studied: 1. Acute E group (rats were given a single dose of E, 4 g/kg as a 25% V/V solution and control received isocaloric dextrose; 2 hour prior to study). 2. Chronic E group (rats were fed Leiber-DeCarli 5% ethanol diet from the 4th to 20th day of pregnancy and controls were isocalorically pair fed). On the 20th day of pregnancy, 2 μci of 65Zn was injected intravenously and tissue samples were obtained 10 min. thereafter by caesarean section. Transport of Zn was expressed as percent uptake of injected 65Zn per gm of placental or fetal tissue. Acute E did not affect fetal and placental weights, however, chronic E feeding resulted in 30% decrease in fetal weight (p < 0.05) and 18% increase in placental weight (p < 0,05). Both acute and chronic E caused a significant decrease, 40% and 30% (p < 0.05) in placental and fetal 65Zn uptake respectively. Our results indicate that maternal to fetal Zn transport is depressed by E because of a defect in placental transport of zinc. These results may explain partly the GR seen in FAS.