Pharmacokinetics of morphine and its surrogates XI: Effect of simultaneously administered naltrexone and morphine on the pharmacokinetics and pharmacodynamics of each in the dog

Abstract

There were no dramatic modifications of the pharmacokinetics in the dog of i.v. bolus doses of 0·5, 2·7 and 5 mg kg⁻¹ morphine by coadministering i.v. 5 mg kg⁻¹ naltrexone as bolus injections over 15–20s and 12·3 mg kg⁻¹ by continuous infusion. Morphine's terminal half‐life, clearances, apparent volumes of distribution (except for that of the central compartment), percentages of drug and conjugated metabolite excreted in urine and bile did not differ significantly by paired t‐test (probability (p) > 0·5 for rejection of the null hypothesis of no difference) when naltrexone was coadministered. There were no statistically significant (by t‐test) modifications of the plasma pharmacokinetics in the dog of i.v. bolus doses of 5 mg kg⁻¹ naltrexone with and without morphine coadministration except for the coefficient of the second (or terminal) exponential of the sum that fitted the plasma concentration‐time data of naltrexone. Although morphine coadministration did not significantly affect the terminal half‐life of naltrexone, its clearances or apparent volumes of distribution by t‐test of the differences between averages (with each dog equally weighted), drug coadministration did significantly (by t‐test) affect the fraction of naltrexone dose secreted into bile as conjugate (f_B), the fraction of the dose excreted as conjugate in urine, and the fraction excreted elsewhere (f_B). Although naltrexone reversed the central action of morphine in affecting monitored pupil diameters, it did not antagonize the peripheral effects of morphine in perturbing renal and biliary flow rates. This led to a larger fraction of the naltrxone does being metabolized to conjugate on morphine coadministration. Since less naltrexone conjugate was renally and biliary excreted initially, due to morphine inhibition of the initial renal and biliary processes, naltrexone conjugate plasma concentrations were higher when morphine was coadministered.