Richard M. Welch

Analgesie drugs in breast milk and plasma

The disposition of salicylic acid, phenacetin, caffeine, and codeine, and two metabolites, acetaminophen and morphine, was studied in breast milk and plasma of two lactating mothers after single oral doses of a compound analgesic. Salicylic acid penetrated poorly into milk, with peak levels of only 1.12 to 1.69 µg/ml, whereas peak plasma levels were 33 to 43.4 µg/ml. The drug was also eliminated more slowly from milk than plasma. In contrast, caffeine and phenacetin kinetics in breast milk and plasma were similar, but milk levels were somewhat lower than plasma levels in both subjects. Metabolically produced acetaminophen levels in both fluids were much higher than those of the parent drug, phenacetin, in one subject, but early plasma and milk phenacetin levels exceeded those of acetaminophen in the other subject, thereafter dropping sharply to assume the pattern of the first subject. Elimination of the metabolite, acetaminophen, from milk was slower than from plasma (subject 1, half‐life (t½) of drug in milk, 4.7 hr; t½ in plasma, 2.9 hr). In both subjects codeine concentrations in milk were 1.5 to 2.4 times as high as in plasma at the same times after drug. Metabolically produced morphine levels in milk from both mothers were low but exceeded those in plasma after 1 hr. Calculations based on average milk concentrations over the 12 hr after drug in subject 1 revealed milk excretion of 0.7% or less of the ingested dose of each drug. Similar calculations based on predicted steady‐state milk drug concentrations in subject 2 indicated maximum milk excretion of 2.7% of the dose. In each case caffeine was excreted in the milk in the greatest amount.

Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and β‐phase elimination half‐lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 nglml (aspirin‐codeine phosphate administration) and 7.4 ng/ml (acetaminophen‐codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration‐time curves for morphine and codeine was 0.095 for the aspirin‐codeine phosphate study and 0.12 for the acetaminophen‐codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Cigarette smoke: Stimulatory effect on metabolism of 3,4-benzpyrene by enzymes in rat lung

Abstract The enzymatic hydroxylation of 3,4-benzpyrene (BP) by lung was increased 34% and 186% in rats exposed to cigarette smoke for 2 or 4 hours, respectively. Induction of BP-hydroxylase in lung by cigarette smoke was completely blocked by actinomycin D or puromycin. An increase in BP-hydroxylase activity was also observed in various organs of pregnant rats exposed to cigarette smoke 5 hours daily for 3 days. The most marked increases were observed in the lung (12-fold) and placenta (4-fold), although increases were also observed in the intestine and in maternal and fetal liver.

Pharmacological significance of the species differences in bupropion metabolism

Bupropion provided a dose-dependent prevention of tetrabenazine-induced sedation in mice but not rats. Bupropion was extensively metabolized in mice, rats, dogs and man. About 85% of the dose was excreted in urine of rats and man. The predominant metabolites in rat urine were side chain cleavage products of bupropion (m-chlorobenzoic acid) with a minor fraction consisting of basic side chain hydroxylated metabolites. Mice, dogs and man form a major side chain hydroxylated product (BW 306U) which appeared in higher concentration than bupropion in plasma of these species but not rats. The relatively high plasma levels of BW 306U in mice but not rats may account for the species difference in pharmacological response observed with bupropion.

The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium, in human and rat plasma.

To assess the mechanism and rate of in vitro degradation of cisatracurium in aqueous buffer and in human and rat plasma.

Codeine kinetics as determined by radioimmunoassay.

Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 nglm!) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 nglmt) appeared within 0.75 to I hr. The mean plasma t1;2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5. I Llkg, respectively. Oral, relative to intramuscular, bioavailability qf codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).

Nasal Decongestant Activity of Pseudoephedrine

The effectiveness of orally administered pseudoephedrine in patients with acute or chronic nonsuppurative rhinitis was evaluated under double-blind conditions. Intranasally administered ephedrine which was given to all patients at the end of this study served as the positive control. Marked nasal decongestant effects of a single oral dose of pseudoephedrine (60 mg tablet), as determined by a modified passive anterior, rhinometrie technique occurred within 30 minutes and were maintained for at least four hours. The mean nasal decongestant response (Δ% of baseline) of 57.2% was associated with a mean peak, plasma pseudoephedrine level of 274 ng/ml. In addition, the maximum response to oral pseudoephedrine treatment was equivalent to the response produced by ephedrine nasal spray. These results suggest that pseudoephedrine is an orally effective nasal decongestant.

Effect of Aroclor 1254, phenobarbital, and polycyclic aromatic hydrocarbons on the plasma clearance of caffeine in the rat

A thin‐layer chromatographic method is described for the quantitation of caffeine and its dimethylxanthine metabolites, theophylline, theobromine, and paraxanthine. The method was used to evaluate the effect of polycyclic aromatic hydrocarbons (PCH), polychlorinated biphenyls (Aroclor 1254), or phenobarbital on the pharmacokinetics of caffeine and its dimethylxanthine metabolites. The oral administration of benzo[a] pyrene (BP) or Aroclor 1254 to rats for 3 days markedly increased the plasma clearance of caffeine and its dimethylxanthine metabolites. Similar results on the plasma clearance of caffeine were obtained with benzanthracene, dibenzanthracene, chrysene, or pyrene. Although the elimination of caffeine from plasma was increased in rats treated with phenobarbital for 3 days, it was less effective in this respect than the PCH or Aroclor 1254. In addition, phenobarbital did not significantly affect the rate of elimination of the dimethylxanthine metabolites from rat plasma following an intravenous dose of caffeine. Following the intravenous administration of caffeine to rats pretreated with Aroclor 1254 or BP, there was a marked increase in the appearance of theophylline, theobromine, and paraxanthine in plasma. The time to achieve peak plasma levels of these metabolites was reduced from 6 to 7 hr in control rats to I hr in Aroclor 1254‐treated rats and to less than 3 hr in rats treated with BP. Moreover, the plasma elimination of the dimethylxanthine metabolites formed from caffeine was greatly accelerated after pretreatment with BP or Aroclor 1254. A dose‐response study with BP indicated that as little as 1.0 mglkg of BP administered orally for 3 days markedly increased the plasma clearance of caffeine; however, pretreatment with BP did not affect the absolute bioavailability of caffeine. The area under the caffeine plasma curve after oral administration was identical to the area when the same dose was administered intravenously. The above studies indicate that the plasma clearance of caffeine is markedly increased in rats pretreated with phenobarbital, PCH, or Aroclor 1254 and suggest that the metabolism and pharmacology of caffeine may be considerably altered in human subjects exposed to these substances.

Excretion of drugs in human breast milk

The present report briefly discusses some of the morphological, physiological, and compositional aspects of animal and human breast milk and how these characteristics might be important for the accumulation of drugs and foreign compounds. In addition, a study is described confirming the presence of caffeine, codeine, morphine, phenacetin, acetaminophen, and salicylic acid in the breast milk of a lactating mother following oral administration of a combination analgesic containing aspirin, phenacetin, caffeine, and codeine. Although the study is limited to one subject, it has provided critically needed data on the rates of appearance in, and elimination of these drugs from, breast milk. A similar amount of information is presented on phenacetin, also a component of the analgesic mixture, which has not been previously reported to enter human milk. The distribution of these drugs between the slightly more acidic breast milk and the relatively neutral plasma is consistent with their weakly basic, acidic, or relatively neutral properties. In general, the study shows that codeine and morphine milk concentrations are higher than, salicylic acid milk levels are much lower than, and phenacetin, caffeine, and acetaminophen milk concentrations are relatively similar to their respective plasma levels. It is projected, from estimated steady-state milk concentrations of the drugs and their metabolites studied, that very low percentages of the therapeutic dosages (less than 0.7%) would be excreted in mothers milk, too low an amount to be clinically significant to the infant.

Potentiation of the Anti-Inflammatory and Analgesic Activity of Aspirin by Caffeine in the Rat

Summary Caffeine has been found to potentiate the acute anti-inflammatory activity of aspirin, indomethacin, and phenylbuta-zone, but not the activity of sodium salicy-late or hydrocortisone, in the carrageenan pleurisy or hindlimb models of inflammation in the rat. The mobilization of inflammatory cells was not affected by aspirin in the presence or absence of caffeine. The mild analgesia produced by aspirin was confined to a hyperalgesic test in which this drug was able to reduce inflammation and concomitant hyperalgesia and thereby produce an “apparent” analgesic effect. This “apparent” analgesia produced by aspirin was potentiated by caffeine. The mechanism responsible for the potentiated anti-inflammatory and mild analgesic activity of aspirin remains unknown since caffeine did not alter the plasma salicylate levels or prostaglandin synthetase inhibition produced by aspirin. The authors wish to thank Dr. R. A. Maxwell and Dr. D. H. Namm for their advice and constructive criticism in the preparation of this manuscript.