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Biomedical subjects

R V Patwardhan

Publications and source records attributed to R V Patwardhan.

27 records · Page 2Linked to original sources
PubMed1980

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

Ethanol 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 less than 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 less than 0.05) after ethanol. Ethanol also lowered the plasma binding of chlordiazepoxide from 94.7 +/- 0.6% to 93.4 +/- 1.3% (P less than 0.05). The plasma clearance of unbound chlordiazepoxide fell from 468 +/- 51 ml/min to 264 +/- 98 ml/min (P less than 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.

Adult↗
PubMed1980

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 less than 0.05). The plasma binding of caffeine was also lower in cirrhotics (31.3 +/- 1.8% vs 25.5 +/- 4.0%, P less than 0.01). The plasma clearance of unbound caffeine therefore was reduced from 2.0 +/- 0.7 ml/min/kg in controls to 1.2 +/- 0.4 ml/min/kg (P less than 0.01) in cirrhotics, demonstrating impaired elimination of caffeine in cirrhosis.

Adolescent↗
PubMed1980

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, diaxepam, 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.

Blood Proteins↗
PubMed1980

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.

Adult↗
PubMed1980

Cimetidine spares the glucuronidation of lorazepam and oxazepam.

Lorazepam (Ativan) disposition and elimination were studied in 8 normal subjects before and after 1 wk of cimetidine therapy, 300 mg taken orally four times a day. In 4 of these 8 normal subjects the disposition and elimination of oxazepam (Serax) were also studied before and after similar treatment with cimetidine. Cimetidine did not alter the elimination of either lorazepam or oxazepam. Since both drugs are eliminated exclusively after conjugation as glucuronide, this study demonstrates a relative sparing of this pathway of biotransformation of drugs in subjects receiving cimetidine.

Adult↗
PubMed1980

Impaired elimination of caffeine by oral contraceptive steroids.

The effect of OCS on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 13 healthy males, nine healthy females taking no OCS, and nine healthy females on OCS. The t1/2 (beta) was significantly prolonged in women on OCS (10.7 +/- 3.0 hr vs. 6.2 +/- 1.6) (p less than 0.001) as compared to women taking no OCS. Women on OCS had a significantly lower total plasma clearance (0.79 +/- 0.21 ml/min/kg vs. 1.3 +/- 0.35) and free clearance (1.12 +/- 0.28 ml/min/kg vs. 1.97 +/- 0.57) that women not taking OCS. Volumes of distribution and plasma binding were similar in both groups of females. When women taking no OCS were compared with men, all pharmacokinetic parameters were similar except for volume of distribution, which was significantly larger in the women (p less than 0.05). We conclude that OCS impair the elimination of caffeine.

Absorption↗
PubMedDate not supplied

Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines.

The effects of oral contraceptive steroids (OCS) on the disposition and elimination of lorazepam, oxazepam, and chlordiazepoxide were examined. Lorazepam and oxazepam are metabolized via glucuronidation while chlordiazepoxide is metabolized by oxidation in the liver. The disposition and elimination of lorazepam, oxazepam, and chlordiazepoxide was studied in females not taking OCS and females taking OCS (norethindrone acetate, 1 mg; ethinyl estradiol, 50 micrograms) for 6 months or more. The t1/2 (beta) for lorazepam was significantly reduced in women taking OCS (6.0 +/- 3.1 vs. 14.0 +/- 6.2 hr) (p less than 0.005) as compared to controls, and the t1/2 (beta) for oxazepam was reduced in women taking OCS (7.71 +/- 3.23 vs. 12.09 +/- 5.08 hr) as compared to controls, but did not reach statistical significance. The plasma clearance of both lorazepam and oxazepam was significantly increased in women taking OCS [(288.9 +/- 165.9 vs. 77.5 +/- 3.29 ml per min) (p less than 0.01) and (251.2 +/- 106.9 vs. 97.86 +/- 69.4 ml per min) (p less than 0.01), respectively] as compared to controls. The volumes of distribution of lorazepam and oxazepam were significantly increased in women taking OCS (p less than 0.05) while plasma binding of these drugs was similar in both groups. In contrast, the t1/2 (beta) of chlordiazepoxide was significantly prolonged (20.58 +/- 8.08 vs. 11.63 +/- 5.91 hr) (p less than 0.05), and the plasma clearance was significantly reduced (13.41 +/- 4.69 vs. 33.22 +/- 12.37 ml per min) (p less than 0.05) in the OCS group as compared to controls. The volumes of distribution of chlordiazepoxide were similar in both groups, and the plasma binding of chlordiazepoxide tended to be lower in the OCS group but did not reach statistical significance. We conclude that OCS exert a differential effect on the elimination of benzodiazepines, whereby oxidation of chlordiazepoxide is impaired while the glucuronidation of lorazepam and oxazepam is enhanced by OCS.

Adult↗