EFFECTS OF ACUTE AND CHRONIC DIPHENHYDRAMINE/ADMINISTRATION ON METHAQUALONE DISPOSITION
Date
1982
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ORCID
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Degree Level
Masters
Abstract
Because of the frequent prescribing of diphenhydramine by physicians for treating allergy and cold, interaction of the antihistamine with other drugs is a concern. Diphenhydramine has
been reported to inhibit drug metabolism on acute administration (Kato, et al., 1964; LeGatt et al., 1980) and stimulate enzyme activities following chronic treatment (Kato et al., 1964;
Conney et al., 1960). On the contrary, there are studies reporting a lack of the acute inhibitory effect (Hindmarsh et al., 1983) and chronic inductive effect (Hunninghake and Azarnoff, 1969) of diphenhydramine on drug metabolism.
To clarify these discrepancies of diphenhydramine on drug metabolism, acute and chronic diphenhydramine-methaqualone interactions were examined in the present investigation.
Methaqualone blood levels were monitored (analyzed by gas-liquid chromatography) to reflect any effects of diphenhydramine on methaqualone metabolism.
To investigate the acute effect of diphenhydramine on methaqualone metabolism, methaqualone (40 mg/kg) alone orally (Control group) or in combination with diphenhydramine (5 mg/kg) either orally (Oral-diphenhydramine group) or intraperitoneally (IP-diphenhydramine group) was administered to rats. A comparison of the effect of the two routes of administration of diphenhydramine on methaqualone metabolism was to verify the previous investigation that diphenhydramine inhibits the intestinal metabolism of methaqualone (LeGatt et al., 1980). Methaqualone blood levels were significantly greater in the oral diphenhydramine group and the IP-diphenhydramine group than the control group at 60 minutes and 120 minutes after dosing. Methaqualone blood levels were also significantly greater in the oral-diphenhydramine than the IP-diphenhydramine group at 30 and 60 minutes after dosing. In addition, time required to achieve the maximum methaqualone blood concentration (tmax) is 30 minutes in the control group and 60 minutes in both diphenhydramine treated groups.
Both oral and intraperitoneal administration of diphenhydramine caused changes in blood levels of orally administered methaqualone. Diphenhydramine given orally had a greater effect on methaqualone blood levels than diphenhydramine given intraperitoneally. The data suggested that the gastrointestinal tract is a site of diphenhydramine-methaqualone interaction. However, the changes in methaqualone blood levels caused by intraperitoneally administered diphenhydramine indicate that mechanisms other than inhibition of intestinal methaqualone metabolism are also involved. The delay in tmax observed in diphenhydramine treated groups suggests that other possible mechanisms of interaction may include an interference with methaqualone absorption by diphenhydramine (both oral and intraperitoneal routes), presumably by its centrally mediated anticholinergic properties, and possibly a dose-dependent inhibition of hepatic methaqualone metabolism by diphenhydramine.
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Degree
Master of Science (M.Sc.)
Department
Pharmacy