Pharmacokinetic modeling of over-the-counter drug diphenhydramine self-administered in overdoses in Japanese patients admitted to hospital

Table 4 Physiological, experimental, and final calculated parameters for the diphenhydramine PBPK model established in this study

Parameter	Value for diphenhydramine
Model input parameters
Molecular weight	255
Octanol–water partition coefficient	3.45
Plasma unbound fraction	0.216
Blood–plasma concentration ratio	0.898
Liver–plasma concentration ratio	3.27
Fraction absorbed × intestinal availability	0.436
Absorption rate constant, 1/h	1.36 ± 0.01 ^a
Transfer rate constant (k₁₂)_, 1/h	0.107 ± 0.001 ^a
Transfer rate constant (k₂₁)_, 1/h	0.0437 ± 0.0001 ^a
Volume of systemic circulation, L	117 ± 1
Hepatic intrinsic clearance, L/h	100 ± 1
Hepatic clearance, L/h	17.7
Renal clearance, L/h	0.3
Estimated levels
C_max in plasma, ng/mL	0.209 (1.07) ^b
AUC in plasma, ng h/mL	1.46 (1.07) ^b
C_max in liver, ng/mL	2.93
AUC in liver ng h/mL	10.7
C_max in kidney, ng/mL	1.43
AUC in kidney ng h/mL	9.96
Reported values [12, 13]
Maximum drug concentration time, h [12]	2.5
C_max in plasma, ng/mL [12]	0.195
AUC in plasma, ng h/mL [12]	1.36
Half-life, h [12]	12
Bioavailability [12]	0.34
Urinary excretion of unchanged drug [13]	0.01 ^c

The plasma unbound fraction, octanol–water partition coefficient, blood-to-plasma concentration ratio, and liver-to-plasma concentration ratio of diphenhydramine were estimated using in silico tools [14]
^aData are means ± standard deviations by fitting to measured concentrations
^bValues in parentheses of estimated levels are ratios to the reported values taken from the literature (shown in Fig. 1A, [12]) after 0.1 mg administrations
^c Urinary excretion ratio was taken from the literature [13] after 100 mg administrations

ISSN: 2055-0294